Pyrimidinone compounds

ABSTRACT

Pyrimidinone compounds of formula (10 are inhibitors of the enzyme Lp-PLA 2  and of use in therapy, in particular for treating atherosclerosis.

This application is a divisional of application Ser. No. 10/030,661filed Apr. 22, 2002 now U.S. Pat. No. 6,953,803, which is the NationalStage of International Application No. PCT/EP00/03727 filed on Apr. 25,2000.

The present invention relates to certain novel pyrimidinone compounds,processes for their preparation, intermediates useful in theirpreparation, pharmaceutical compositions containing them and their usein therapy, in particular in the treatment of atherosclerosis.

WO 95/00649 (SmithKline Beecham plc) describe the phospholipase A2enzyme Lipoprotein Associated Phospholipase A₂ (Lp-PLA₂), the sequence,isolation and purification thereof, isolated nucleic acids encoding theenzyme, and recombinant host cells transformed with DNA encoding theenzyme. Suggested therapeutic uses for inhibitors of the enzyme includedatherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardialinfarction, reperfusion injury and acute and chronic inflammation. Asubsequent publication from the same group further describes this enzyme(Tew D et al, Arterioscler Thromb Vas Biol 1996: 16;591–9) wherein it isreferred to as LDL-PLA₂. A later patent application (WO 95/09921, IcosCorporation) and a related publication in Nature (Tjoelker et al, vol374, 6 Apr. 1995, 549) describe the enzyme PAF-AH which has essentiallythe same sequence as Lp-PLA₂ and suggest that it may have potential as atherapeutic protein for regulating pathological inflammatory events.

It has been shown that Lp-PLA₂ is responsible for the conversion ofphosphatidylcholine to lysophosphatidylcholine, during the conversion oflow density lipoprotein (LDL) to its oxidised form. The enzyme is knownto hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to givelysophosphatidylcholine and an oxidatively modified fatty acid. Bothproducts of Lp-PLA₂ action are biologically active withlysophosphatidylcholine, a component of oxidised LDL, known to be apotent chemoattractant for circulating monocytes. As such,lysophosphatidylcholine is thought play a significant role inatherosclerosis by being responsible for the accumulation of cellsloaded with cholesterol ester in the arteries. Inhibition of the Lp-PLA₂enzyme would therefore be expected to stop the build up of thesemacrophage enriched lesions (by inhibition of the formation oflysophosphatidylcholine and oxidised free fatty acids) and so be usefulin the treatment of atherosclerosis.

The increased lysophosphatidylcholine content of oxidatively modifiedLDL is also thought to be responsible for the endothelial dysfunctionobserved in patients with atherosclerosis. Inhibitors of Lp-PLA₂ couldtherefore prove beneficial in the treatment of this phenomenon. AnLp-PLA₂ inhibitor could also find utility in other disease states thatexhibit endothelial dysfunction including diabetes, hypertension, anginapectoris and after ischaemia and reperfusion.

In addition, Lp-PLA₂ inhibitors may also have a general application inany disorder that involves activated monocytes, macrophages orlymphocytes, as all of these cell types express Lp-PLA₂. Examples ofsuch disorders include psoriasis.

Furthermore, Lp-PLA₂ inhibitors may also have a general application inany disorder that involves lipid oxidation in conjunction with Lp-PLA₂activity to produce the two injurious products, lysophosphatidylcholineand oxidatively modified fatty acids. Such conditions include theaforementioned conditions atherosclerosis, diabetes, rheumatoidarthritis, stroke, myocardial infarction, reperfusion injury and acuteand chronic inflammation. Further such conditions include vari usneuropsychiatric disorders such as schizophrenia (see PsychopharmacologyBulletin, 31, 159–165, 1995).

Patent applications WO 96/12963, WO 96/13484, WO96/19451, WO 97/02242,WO97/217675, WO97/217676, WO 96/41098, and WO97/41099 (SmithKlineBeecham plc) disclose inter alia various series of4-thionyl/sulfinyl/sulfonyl azetidinone compounds which are inhibitorsof the enzyme Lp-PLA₂. These are irreversible, acylating inhibitors (Tewet al, Biochemistry, 37, 10087, 1998).

Patent applications WO 99/24420 and WO 00/10980 (SmithKline Beecham plc,published after the priority date of the present application) describe anew class of reversible, non-acylating inhibitors of the enzyme Lp-PLA₂,in particular a class of pyrimidone compounds. The early2-(alkylthio)pyrimidin-4-one chemical lead is described in Bioorganicand Medicinal Chemistry Letters, 2000, 10, 395–8.

A further class of pyrimidone compounds has now been identified whichare inhibitors of the enzyme Lp-PLA₂.

Accordingly, the present invention provides a compound of formula (I):

in which:

-   -   R¹ is an aryl or heteroaryl group, optionally substituted by 1,        2, 3 or 4 substituents which may be the same or different        selected from C₍₁₋₁₈₎alkyl C₍₁₋₁₈₎alkoxy, C₍₁₋₁₈₎alkylthio,        arylC₍₁₋₁₈₎alkoxy, hydroxy, halogen, CN, COR⁶, carboxy, COOR⁶,        CONR⁹R¹⁰, NR⁶COR⁷, SO₂NR⁹R¹⁰, NR⁶SO₂R⁷, NR⁹R¹⁰, mono to        perfluoro-C₍₁₋₄₎alkyl and mono to perfluoro-C₍₁₋₄₎alkoxy, or, as        a single substituent, optionally in combination with a further        substituent as hereinbefore defined, CH₂COOH or a salt thereof,        CH₂COOR⁸, CH₂CONR⁹R¹⁰, CH₂CN, (CH₂)_(m)NR⁹R¹⁰, (CH₂)_(m)OH or        (CH₂)_(m)OR⁶ where m is an integer from 1 to 3;    -   R² is an aryl or heteroaryl group, optionally substituted by 1,        2, 3 or 4 substituents which may be the same or different        selected from C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy, C₍₁₋₁₈₎alkylthio,        arylC₍₁₋₁₈₎alkoxy, hydroxy, halogen, CN, COR⁶, carboxy, COOR⁶,        CONR⁹R¹⁰, NR⁶COR⁷, SO₂NR⁹R¹⁰, NR⁶SO₂R⁷, NR⁹R¹⁰, mono to        perfluoro-C₍₁₋₄₎alkyl, mono to perfluoro-C₍₁₋₄₎alkoxy, and        arylC₍₁₋₄₎alkyl;    -   R³ is hydrogen or C₍₁₋₄₎alkyl which may be unsubstituted or        substituted by hydroxy, OR⁶, COR⁶, carboxy, COOR⁶, CONR⁹R¹⁰,        NR⁹R¹⁰, mono- or di-(hydroxyC₍₁₋₆₎alkyl)amino or        N-hydroxyC₍₁₋₆₎alkyl-N—C₍₁₋₆₎alkyl amino;    -   R⁴ is an aryl or a heteroaryl ring optionally substituted by 1,        2, 3 or 4 substituents which may be the same or different        selected from C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy, C₍₁₋₁₈₎alkylthio,        arylC₍₁₋₁₈₎alkoxy, hydroxy, halogen, CN, COR⁶, carboxy, COOR⁶,        CONR⁹R¹⁰, NR⁶COR⁷, SO₂NR⁹R¹⁰, NR⁶SO₂R⁷, NR⁹R¹⁰, mono to        perfluoro-C₍₁₋₄₎alkyl and mono to perfluoro-C₍₁₋₄₎alkoxy;    -   R⁵ is an aryl ring which is further optionally substituted by 1,        2, 3 or 4 substituents which may be the same or different        selected from C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy, C₍₁₋₁₈₎alkylthio,        arylC₍₁₋₁₈₎alkoxy, hydroxy, halogen, CN, COR⁶, carboxy, COOR⁶,        CONR⁹R¹⁰, NR⁶COR⁷, SO₂NR⁹R¹⁰, NR⁶SO₂R⁷, NR⁹R¹⁰, mono to        perfluoro-C₍₁₋₄₎alkyl and mono to perfluoro-C₍₁₋₄₎alkoxy;    -   R⁶ and R⁷ are independently hydrogen or C₍₁₋₂₀₎alkyl, for        instance C₍₁₋₄₎alkyl (e.g. methyl or ethyl);    -   R⁸ is C₍₁₋₄₎alkyl or a pharmaceutically acceptable in vivo        hydrolysable ester group;    -   R⁹ and R¹⁰ which may be the same or different is each selected        from hydrogen, C₍₁₋₁₂₎alkyl, CH₂R¹¹, CHR¹²CO₂H or a salt        thereof, or R⁹ and R¹⁰ together with the nitrogen to which they        are attached form a 4- to 7-, preferably 5- to 7-, membered ring        optionally containing one or more further heteroatoms selected        from oxygen, nitrogen and sulphur, and optionally substituted by        one or two substituents selected from hydroxy, oxo, C₍₁₋₄₎alkyl,        C₍₁₋₄₎alkylCO, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for        instance morpholine or piperazine;    -   R¹¹ is COOH or a salt thereof, COOR⁸, CONR⁶R⁷, CN, CH₂OH or        CH₂OR⁶;    -   R¹² is an amino acid side chain such as CH₂OH from serine;    -   n is an integer from 1 to 4, preferably 1 or 3;    -   X is O or S; and    -   Z is CR¹³R¹⁴ where R¹³ and R¹⁴ are each hydrogen or C₍₁₋₄₎alkyl,        or R¹³ and R¹⁴ together with the intervening carbon atom form a        C₍₃₋₆₎cycloalkyl ring.

Preferably, Z is CH₂.

Representative examples of R¹ when an aryl group include phenyl andnaphthyl.

Representative examples of R¹ when a heteroaryl group include a 5- or6-membered, monocyclic heteroaryl group comprising 1 or 2 nitrogenheteroatoms.

Preferably, R¹ is pyrimidyl optionally substituted by 1 or 2substituents preferably selected from oxo, arylC₍₁₋₄₎alkyl (e.g.benzyl), C₍₁₋₆₎alkyl (e.g. methyl or ethyl), C₍₃₋₆₎cycloalkyl, hydroxy,C₍₁₋₄₎alkoxy (e.g. methoxy), carboxyC₍₁₋₆₎alkyl,C₍₁₋₆₎alkylcarboxyC₍₁₋₆₎alkyl, di-C₍₁₋₆₎alkylamino, and morpholino; orpyrazolyl optionally substituted by C₍₁₋₆₎alkyl (e.g. methyl or ethyl).

Preferably, ZR¹ is pyrimid-5-ylmethyl optionally substituted by2-methoxy, 2-trifluoromethyl, 2-(4-morpholino) or 2-dimethylamino;2-oxo-pyrimid-5-ylmethyl or 1-methyl-4-pyrazolylmethyl.

Preferably X is S.

Representative examples of R² when an aryl group include phenyl andnaphthyl. Representative examples of R² when a heteroaryl group includepyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, quinolyl,benzothiazolyl, pyridazolyl and pyrazinyl. Preferably, R² is phenyloptionally substituted by halogen.

Representative examples of R²CH₂X include 4-fluorobenzylthio.

Representative examples of R³ include hydrogen; and methyl, ethyl andpropyl, optionally substituted by amino, C₍₁₋₃₎alkylamino, diC₍₁₋₃₎alkyl amino, hydroxyC₍₁₋₃₎alkylamino, hydroxy, C₍₁₋₃₎alkoxy,carboxy, C₍₁₋₃₎alkylcarboxy, and heterocycyl such as piperidino,piperazino, pyrrolidono and morpholino, wherein the alkyl moiety, ifpresent, is,preferably methyl, or ethyl.

Representative examples of R⁴ include phenyl optionally substituted byhalogen; thiophene; pyridine; and pyrimidine.

Representative examples of R⁵ include phenyl optionally substituted byhalogen, trifluoromethyl, or trifluoromethoxy, preferably at the4-position.

Preferably, R⁴ and R⁵ together form a 4-(phenyl)phenyl substituent inwhich the remote phenyl ring may be optionally substituted by halogen ortrifluoromethyl, preferably at the 4-position.

Pharmaceutically acceptable in vivo hydrolysable ester groups for R⁸include those which break down readily in the human body to leave theparent acid or its salt.

Representative examples of values of pharmaceutically acceptable in vivohydrolysable ester groups for R⁸ include:

-   —CH(R^(a))O.CO.R^(b);-   —CH(R^(a))O.CO.OR^(c);-   —CH(R^(a))CO.NR^(e)R^(f)-   —R^(d)NR^(e)R^(f);-   —CH₂OR^(g);

-   CH(R^(a))O.CO.C₆H₄Y¹COCH(R^(i))NH₂; and

in which:

-   R^(a) is hydrogen, (C₁₋₆)alkyl, in particular methyl,    (C₃₋₇)cycloalkyl, or phenyl, each of which may be optionally    substituted;-   R^(b) is (C₁₋₆)alkyl, (C₁₋₆)alkoxy(C₁₋₆)alkyl, phenyl, benzyl,    (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl(C₃₋₇)cycloalkyl, 1-amino(C₁₋₆)alkyl,    or 1-(C₁₋₆alkyl)amino(C₁₋₆)alkyl, each of which may be optionally    substituted; or-   R^(a) and R^(b) together form a 1,2-phenylene group optionally    substituted by one or two methoxy groups;-   R^(c) is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₆)alkyl(C₃₋₇)cycloalkyl;-   R^(d) is (C₁₋₆)alkylene optionally substituted with a methyl or    ethyl group;-   R^(e) and R^(f) which may be the same or different is each    (C₁₋₆)alkyl; or aryl(C₁₋₄)alkyl, optionally substituted with e.g.    hydroxy;-   R^(g) is (C₁₋₆)alkyl;-   R^(h) is hydrogen, (C₁₋₆)alkyl or phenyl;-   R^(i) is hydrogen or phenyl optionally substituted by up to three    groups selected from halogen, (C₁₋₆)-alkyl, or (C₁₋₆)alkoxy;    and-   Y¹ is oxygen or NH;    for instance:-   (a) acyloxyalkyl groups such as acetoxymethyl, isobutyryloxymethyl,    pivaloyloxymethyl, benzoyloxymethyl, α-acetoxyethyl,    α-pivaloyloxyethyl, 1-(cyclohexylcarbonyloxy)ethyl,    (1-aminoethyl)carbonyloxymethyl,    2-methoxyprop-2-ylcarbonyloxymethyl, phenylcarbonyloxymethyl and    4-methoxyphenyl-carbonyloxymethyl;-   (b) alkoxy/cycloalkoxycarbonyloxyalkyl groups, such as    ethoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl,    cyclohexyloxycarbonyloxymethyl,    1-methylcyclohexyloxycarbonyloxymethyl and α-ethoxycarbonyloxyethyl;-   (c) dialkylaminoalkyl, especially di-loweralkylamino alkyl groups    such as dimethylaminoethyl, dimethylaminoethyl, diethylaminomethyl    or diethylaminoethyl;-   (d) acetamido groups such as N,N-dimethylaminocarbonylmethyl,    N,N-(2-hydroxyethyl)aminocarbonylmethyl;-   (e) lactone groups such as phthalidyl and dimethoxyphthalidyl;-   (f) (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl; and-   (g) (2-methoxycarbonyl-E-but-2-en-yl)methyl.

Representative examples of pharmaceutically acceptable in vivohydrolysable ester groups for R⁸ include:

-   (2-methoxycarbonyl-E-but-2-en-yl)methyl, isobutyryloxymethyl,    2-methoxyprop-2-ylcarbonyloxymethyl, phenylcarbonyloxymethyl,    4-methoxyphenyl-carbonyloxymethyl, t-butyloxycarbonyloxymethyl,    cyclohexyloxy-carbonyloxymethyl,    1-methylcyclohexyloxycarbonyloxymethyl,    N,N-dimethylaminocarbonylmethyl, and    (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl.

It will be appreciated that in some instances, compounds of the presentinvention may include a basic function such as an amino group as asubstituent. Such basic functions may be used to form acid additionsalts, in particular pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts include those described by Berge, Bighley, andMonkhouse, J. Pharm. Sci., 1977, 66, 1–19. Such salts may be formed frominorganic and organic acids. Representative examples thereof includemaleic, fumaric, benzoic, ascorbic, pamoic, succinic,bismethylenesalicylic, methanesulfonic, p-toluenesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric,gluconic, aspartic, stearic, palmitic, itaconic, glycolic,p-aminobenzoic, glutamic, taurocholic acid, benzenesulfonic,hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric andnitric acids.

It will be appreciated that in some instances, compounds of the presentinvention may include a carboxy group as a substituent. Such carboxygroups may be used to form salts, in particular pharmaceuticallyacceptable salts. Pharmaceutically acceptable salts include thosedescribed by Berge, Bighley, and Monkhouse, J. Pharm Sci., 1977, 66,1–19. Preferred salts include alkali metal salts such as the sodium andpotassium salts.

When used herein, the term “alkyl” and similar terms such as “alkoxy”includes all straight chain and branched isomers. Representativeexamples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.

When used herein, the term “aryl” refers to, unless otherwise defined, amono- or bicyclic aromatic ring system containing up to 10 carbon atomsin the ring system, for instance phenyl or naphthyl.

When used herein, the term “heteroaryl” refers to a mono- or bicyclicheteroaromatic ring system comprising up to four, preferably 1 or 2,heteroatoms each selected from oxygen, nitrogen and sulphur. Each ringmay have from 4 to 7, preferably 5 or 6, ring atoms. A bicyclicheteroaromatic ring system may include a carbocyclic ring.

When used herein, the terms “halogen” and “halo” include fluorine,chlorine, bromine and iodine and fluoro, chloro, bromo and iodo,respectively.

Particularly preferred compounds of formula (I) are:

-   1-(N-Methyl-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methylpyrazol-4-ylmethyl)pyrimidin-4-one;-   1-(N-Methyl-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methylpyrazol-4-ylmethyl)pyrimidin-4-one;-   1-(N-(2-Dimethylaminoethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl-2-(4-fluorobenzyl)thio-5-(1-methylpyrazol-4-ylmethyl)pyrimidin-4-one;-   1-(N-Methyl-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-(4-morpholino)pyrimid-5-ylmethyl)pyrimidin-4-one;-   1-(N-(2-(dimethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one;-   1-(N-(2-(diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one;-   1-(N-(2-diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one;-   1-(N-(2-(1-Piperidino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one    bitartrate;-   1-(N-(Carboxymethyl)-N-(4-4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methylpyrazolylmethyl)pyrimidin-4-one    sodium salt; and-   1-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one    or a pharmaceutically acceptable salt thereof, including the    hydrochloride, bitartrate, citrate and tosylate salts.

Since the compounds of the present invention, in particular compounds offormula (I), are intended for use in pharmaceutical compositions, itwill be understood that they are each provided in substantially pureform, for example at least 50% pure, more suitably at least 75% pure andpreferably at least 95% pure (% are on a wt/wt basis). Impurepreparations of the compounds of formula (I) may be used for preparingthe more pure forms used in the pharmaceutical compositions. Althoughthe purity of intermediate compounds of the present invention is lesscritical, it will be readily understood that the substantially pure formis preferred as for the compounds of formula (I). Preferably, wheneverpossible, the compounds of the present invention are obtained incrystalline form.

When some of the compounds of this invention are allowed to crystalliseor are recrystallised from organic solvents, solvent of crystallisationmay be present in the crystalline product. This invention includeswithin its scope such solvates. Similarly, some of the compounds of thisinvention may be crystallised or recrystallised from solvents containingwater. In such cases water of hydration may be formed. This inventionincludes within its scope stoichiometric hydrates as well as compoundscontaining variable amounts of water that may be produced by processessuch as lyophilisation. In addition, different crystallisationconditions may lead to the formation of different polymorphic forms ofcrystalline products. This invention includes within its scope allpolymorphic forms of the compounds of formula (I).

Compounds of the present invention are inhibitors of the enzymelipoprotein associated phospholipase A₂ (Lp-PLA₂) and as such areexpected to be of use in therapy, in particular in the treatment ofatherosclerosis. In a further aspect therefore the present inventionprovides a compound of formula (I) for use in therapy.

The compounds of formula (I) are inhibitors of lysophosphatidylcholineproduction by Lp-PLA₂ and may therefore also have a general applicationin any disorder that involves endothelial dysfunction, for exampleatherosclerosis, diabetes, hypertension, angina pectoris and afterischaemia and reperfusion. In addition, compounds of formula (I) mayhave a general application in any disorder that involves lipid oxidationin conjunction with enzyme activity, for example in addition toconditions such as atherosclerosis and diabetes, other conditions suchas rheumatoid arthritis, stroke, inflammatory conditions of the brainsuch as Alzheimer's Disease, myocardial infarction, reperfusion injury,sepsis, and acute and chronic inflammation. Further such conditionsinclude various neuropsychiatric disorders such as schizophrenia (seePsychopharmacology Bulletin, 31, 159–165, 1995).

Further applications include any disorder that involves activatedmonocytes, macrophages or lymphocytes, as all of these cell typesexpress Lp-PLA₂. Examples of such disorders include psoriasis.

Accordingly, in a further aspect, the present invention provides for amethod of treating a disease state associated with activity of theenzyme Lp-PLA₂ which method involves treating a patient in need thereofwith a therapeutically effective amount of an inhibitor of the enzyme.The disease state may be associated with the increased involvement ofmonocytes, macrophages or lymphocytes; with the formation oflysophosphatidylcholine and oxidised free fatty acids; with lipidoxidation in conjunction with Lp PLA2 activity; or with endothelialdysfunction.

Compounds of the present invention may also be of use in treating theabove mentioned disease states in combination with ananti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti-anginal,anti-inflammatory, or anti-hypertension agent or an agent for loweringLp(a). Examples of the above include cholesterol synthesis inhibitorssuch as statins, anti-oxidants such as probucol, insulin sensitisers,calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs.Examples of agents for lowering Lp(a) include the aminophosphonatesdescribed in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312(Symphar SA and SmithKline Beecham).

A preferred combination therapy will be the use of a compound of thepresent invention and a statin. The statins are a well known class ofcholesterol lowering agents and include atorvastatin, simvarstatin,pravastatin, cerivastatin, fluvastatin, lovastatin and ZD 4522 (alsoreferred to as S-4522, Astra Zeneca). The two agents may be administeredat substantially the same time or at different times, according to thediscretion of the physician.

A further preferred combination therapy will be the use of a compound ofthe present invention and an anti-diabetic agent or an insulinsensitiser, as coronary heart disease is a major cause of death fordiabetics. Within this class, preferred compounds for use with acompound of the present invention include the PPARgamma activators, forinstance G1262570 (Glaxo Wellcome) and also the glitazone class ofcompounds such as rosiglitazone (Avandia, SmithKline Beecham),troglitazone and pioglitazone.

In therapeutic use, the compounds of the present invention are usuallyadministered in a standard pharmaceutical composition. The presentinvention therefore provides, in a further aspect, a pharmaceuticalcomposition comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier.

Suitable pharmaceutical compositions include those which are adapted fororal or parenteral administration or as a suppository.

Suitable pharmaceutical compositions include those which are adapted fororal or parenteral administration or as a suppository. Compounds offormula (I) which are active when given orally can be formulated asliquids, for example syrups, suspensions or emulsions, tablets, capsulesand lozenges. A liquid formulation will generally consist of asuspension or solution of the compound or pharmaceutically acceptablesalt in a suitable liquid carrier(s) for example, ethanol, glycerine,non-aqueous solvent, for example polyethylene glycol, oils, or waterwith a suspending agent, preservative, flavouring or colouring agent. Acomposition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose. A composition in the form of acapsule can be prepared using routine encapsulation procedures. Forexample, pellets containing the active ingredient can be prepared usingstandard carriers and then filled into a hard gelatin capsule;alternatively, a dispersion or suspension can be prepared using anysuitable pharmaceutical carrier(s), for example aqueous gums,celluloses, silicates or oils and the dispersion or suspension thenfilled into a soft gelatin capsule. Typical parenteral compositionsconsist of a solution or suspension of the compound of formula (I) in asterile aqueous carrier or parenterally acceptable oil, for examplepolyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil orsesame oil. Alternatively, the solution can be lyophilised and thenreconstituted with a suitable solvent just prior to administration. Atypical suppository formulation comprises a compound of formula (I)which is active when administered in this way, with a binding and/orlubricating agent such as polymeric glycols, gelatins or cocoa butter orother low melting vegetable or synthetic waxes or fats.

Preferably the composition is in unit dose form such as a tablet orcapsule. Each dosage unit for oral administration contains preferablyfrom 1 to 500 mg (and for parenteral administration contains preferablyfrom 0.1 to 25 mg) of a compound of the formula (I). The daily dosageregimen for an adult patient may be, for example, an oral dose ofbetween 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or anintravenous, subcutaneous, or intramuscular dose of between 0.1 mg and100 mg, preferably between 0.1 mg and 25 mg, of the compound of theformula (I), the compound being administered 1 to 4 times per day.Suitably the compounds will be administered for a period of continuoustherapy, for example for a week or more.

A compound of formula (I) may be prepared by a number of processes whichinclude:

-   (a) reacting a compound of formula (II):

in which X, Y, Z, R¹ and R² are as hereinbefore defined,with a compound of formula (III):R⁵—R⁴—CH₂NHR³  (III)in which R³, R⁴ and R⁵ are as hereinbefore defined; under amide formingconditions;

-   (b) reacting a compound of formula (IV):

in which X, Z, R¹ and R² are as hereinbefore defined,with a compound of formula (V):R⁵—R⁴—CH₂NR³—CO—(CH₂)_(n)-L¹  (V)in which n, R³, R⁴ and R⁵ are as hereinbefore defined, and L¹ is aleaving group such as halogen, for instance bromo or iodo,in the presence of a base such as a secondary or tertiary amine, forinstance di-iso-propylethylamine, in an inert solvent such asdichloromethane;

-   (c) when X is S, reacting a compound of formula (VI):

in which n, Z, R¹, R³, R⁴ and R⁵ are as hereinbefore defined,with a compound of formula (VII):R²—CH₂-L¹  (VII)in which R² and L¹ are as hereinbefore defined,in the presence of a base such as a secondary or tertiary amine, forinstance di-isopropylethylamine, in an inert solvent such asdichloromethane; or

-   (d) when X is O, reacting a compound of formula (VIII):

in which n, Z, R¹, R³, R⁴ and R⁵ are as hereinbefore defined, and L² isa leaving group such as halogen or alkylthio, for instance methylthio,with a compound of formula (IX):R²—CH₂—OH  (IX)in which R² is as hereinbefore defined,in the presence of a base such as 4-dimethylaminopyridine, in an inertsolvent such as pyridine.

Compounds of formulae (II), (IV), (VI) and (VIII) for use in the aboveprocesses may be prepared by processes illustrated in the followingscheme I:

in which:

-   L³ is a C(1–6)alkyl group, for instance methyl;-   R¹⁵ is a C₍₁₋₆₎alkyl group, for instance methyl, ethyl, or t-butyl,    and-   L¹, L², R¹, R², R³, R⁴, R⁵, n, X and Z are as hereinbefore defined.

With reference to Scheme I:

Amide forming conditions for step (a) are well known in the art.Preferably, the acid of formula (II) is reacted with the amine offormula (III) in an inert solvent, such as dichloromethane, at ambienttemperature and in the presence of an activating agent such as as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide plus hydroxybenzotriazole.

Alkylation conditions for step (b) include reaction in the presence of abase such as a secondary or tertiary amine, for instancedi-iso-propylethylamine, in an inert solvent such as dichloromethane,forming an intermediate ester which is converted to the acid of formula(II) by hydrolysis, for instance using aqueous sodium hydroxide in asolvent such as dioxan or by alternative deprotection, for instanceusing trifluoracetic acid in a solvent such as dichloromethane.

Conditions for step (c) include under thioether forming conditions.Advantageously, the reaction is carried out in the presence of a basesuch as sodium ethoxide or potassium carbonate, preferably in a solventsuch as ethanol or dimethyl formamide, or a secondary or tertiary aminebase such as di-isopropylethyl amine, in solvent such asdichloromethane.

In step (d), a compound of formula (XVII) is reacted with thiourea, inthe presence of sodium ethoxide (preferably generated in situ fromsodium and ethanol).

In step (e), a compound of formula (XVIII) is reacted with ethyl formatein the presence of a base such as sodium hydride or potassiumisopropoxide.

In step (f), a compound of formula (IV) is reacted with a compound offormula (V) in the presence of a base such as a secondary or tertiaryamine, for instance di-isopropylethylamine, in an inert solvent such asdichloromethane

In step (g), a compound of formula (XIII) is reacted with a compound offormula (XIV) in a solvent such as dimethylformamide to form anintermediate thiourea, which is then treated with a base such as sodiummethoxide.

In step (h), a compound of formula (XVI) is reacted with a metalthiocyanate, for example potassium thiocyanate, in a solvent such asacetonitrile.

In step (i), a compound of formula (XVII) is reacted with a methylatingagent such as dimethyl sulphate in the presence of a base such aspotassium carbonate, followed by hydrolysis of the intermediate ester inconventional manner e.g. by basic hydrolysis using sodium hydroxide togive the corresponding carboxylic acid which may then be converted intothe acyl chloride, for instance by treatment with oxalyl chloride.

In step (j), a catalyst such as 4-dimethylaminopyridine, and in asolvent such as pyridine are used.

In step (k), a compound of formula (XIII) is reacted with a compound offormula (XV) in a solvent such as dimethylformamide to form anintermediate thiourea, which is then treated with a base such as sodiummethoxide.

The present invention will now be illustrated by the following examples.

EXAMPLES

The structure and purity of the intermediates and examples was confirmedby 1H-NMR and (in nearly all cases) mass spectroscopy, even where notexplicitly indicated below.

Intermediate A1—4-(4-Chorophenyl)benzaldehyde

-   (a) A mixture of 4-formylbenzeneboronic acid (2.50 g, 2 equiv),    4-chloroiodobenzene (1.98 g, 1 equiv),    tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.05 equiv),    aqueous sodium carbonate (18 ml, 2M solution, 2 equiv) and    dimethoxyethane (50 ml) was stirred at reflux under argon overnight,    then cooled and diluted with ethyl acetate. The mixture was filtered    as necessary to remove inorganic residues, then the organic layer    was washed successively with aqueous citric acid and brine, dried    and evaporated. The crude product was purified by chromatography    (silica, 5% ethyl acetate in hexane); product fractions were    evaporated to a white solid (1.32 g, 72%).-   (b) A mixture of 4-chlorobenzeneboronic acid (19.4 g, 1 equiv),    4-bromobenzaldehyde (22.9 g, 1 equiv), palladium(II) acetate (1.4 g,    0.05 equiv) aqueous sodium carbonate (30.3 g in 144 ml solution, 2    equiv) and dimethoxyethane (500 ml) was stirred at reflux under    argon for 2.5 h, then evaporated to low volume and diluted with    dichloromethane. Workup continued as in (a) above to give identical    material (25.2 g, 94%). ¹H-NMR (CDCl₃) δ 10.05 (1H, s), 7.96 (2H,    d), 7.73 (2H, d), 7.57 (2H, d), 7.46 (2H, d); MS (AP+) found    (M+1)=217, C₁₃H₉ ³⁵ClO requires 216.    Intermediate A2—N-Methyl-4-(4-chlorophenyl)benzylamine

A mixture of Intermediate A1 (3.5 g, 1 equiv), methylamine (32.3 ml of a2M solution in THF, 4 equiv) and anhydrous magnesium sulphate (4.47 g, 2equiv) was stirred at room teperature for 16 h, then filtered, the solidwashed thoroughly with ethyl acetate, and the combined filtratesevaporated to a white solid (3.7 g). This imine intermediate wassuspended in ethanol (100 ml), cooled in ice and sodium borohydride(0.61 g, 1 equiv) added portionwise. The ice bath was removed, and themixture stirred for 45 min at room temperature then at 50° C. for 1 h.The solvent was removed in vacuo, water was added to the residue, andthe product extracted into dichloromethane. Drying and evaporation ofthe solvent gave a white solid (3.56 g). ¹H-NMR (CDCl₃) δ 7.51 (4H, d),7.40 (4H, d), 3.79 (2H, s), 2.48 (3H, s); MS (APCI+) found (M+1)=232,C₁₄H₁₄ ³⁵ClN requires 231.

Intermediate A3—N-(2-Diethylaminoethyl)-4-(4-chlorophenyl)benzylamine

A mixture of Intermediate A1 (55.0 g), N,N-diethylethylenediamine (35.6ml), 4A molecular sieve (37 g), and dichloromethane (1100 ml) wasreacted at room temperature under argon for 16 h, with occasionalagitation. The solid was filtered off and washed with dichloromethane,and the combined filtrates evaporated to a yellow foam (72.4 g). Thisintermediate imine was reduced with sodium borohydride (8.7 g) inethanol (850 ml) as described for Intermediate A2, yielding the titlecompound as a yellow oil (72.7 g). ¹H-NMR (CDCl₃) δ 1.70 (2H, t), 2.22(6H, s), 2.33 (2H, t), 2.69 (2H, br, m), 3.83 (2H, s), 7.37–7.43 (4H,m), 7.52–7.56 (4H, m).

Intermediate A4—4-(4-Chlorophenyl)benzyl alcohol

A mixture of Intermediate A1 (1.73 g, 1 equiv), sodium borohydride (0.3g, 1 equiv) and ethanol (20 ml) was stirred until a clear solution wasobtained; a gentle exotherm was observed. The temperature was raised to50° C. and stirring continued for 2 h, then the solvent was removed invacuo, water added to the residue, and the product extracted intodichloromethane. Drying and evaporation of the solvent gave a whitesolid (1.67 g). ¹H-NMR (CDCl₃) δ 1.73 (1H,t), 4.74 (2H, d), 7.2–7.6 (8H,m),.

Intermediate A5—N-(4-(4-Chlorophenyl)benzyl)phthalimide

Intermediate A4 (1.62 g, 1 equiv), phthalimide (1.42 g, 1.3 equiv) andtriphenylphosphine (2.53 g, 1.3 equiv) were dissolved in dry THF (50ml), the solution was cooled in ice, and diethyl azodicarboxylate (1.52ml, 1.3 equiv) was added slowly with stirring. The yellow solution wasstirred for 16 h at room temperature, then the solvent was evaporated.Chromatography (silica, 1:1 dichloromethane/pet. ether) and triturationwith ether gave the desired product (2.03 g, 79%). ¹H-NMR (CDCl₃) δ 4.89(2H, s), 7.36–7.50 (8H, m), 7.69–7.74 (2H, m), 7.82–7.89 (2H, m).

Intermediate A6—4-(4-Chlorophenyl)benzylamine

A mixture of Intermediate A5 (1.98 g, 1 equiv) and hydrazine hydrate(0.55 ml, 2 equiv) in ethanol (40 ml) was heated at reflux for 2 h, thenthe solvent was evaporated. The residue was shaken with dichloromethaneand 0.5M aqueous sodium hydroxide, the aqueous layer re-extracted withdichloromethane, and the combined organic extracts purified bychromatography (silica, 1–3% methanolic ammonia in dichloromethane).Product fractions were evaporated to a white solid (0.53 g, 43%). ¹H-NMR(CDCl₃) δ 3.92 (2H, s), 7.28–7.41 (4H, m), 7.49–7.54 (4H, m).

Intermediate A7—N-Methyl-N-(4-(4-chlorophenyl)benzyl)bromoacetamide

Bromoacetyl bromide (0.123 ml, 1.1 equiv) was added to a well-stirredmixture of Intermediate A2 (0.3 g, 1 equiv), sodium hydroxide (0.06 g,1.2 equiv), water and dichloromethane. Stirring was continued for 3 h atroom temperature, then the phases were separated and the organic layerdried and evaporated. Chromatography (silica, 3:1 hexane/ethyl acetate)gave the desired product as an oil (0.37 g). ¹H-NMR (CDCl₃) δ 7.38–7.68(8H, m), 4.77 (2H, s), 4.07 (2H, s), 3.24 (3H, s); MS (APCI+) found(M+1)=352, C₁₆H₁₅ ⁷⁹Br³⁵ClNO requires 351.

Intermediate A8—5-Hydroxymethyl-2-(4-fluorophenyl)pyridine

A solution of Intermediate A23 (4.63 g) in dry dichloromethane (100 ml)was cooled to −78° C. under argon, then DIBAL-H (26.7 ml, 1.5M solutionin toluene) was added dropwise over 20 min. Stirring was continued for40 min at −78° C., then 2M hydrochloric acid (52 ml) was added dropwiseover 15 min. The solution was allowed to warm slowly to roomtemperature, then the organic layer was separated, washed with water,dried and evaporated. Chromatography (silica, 1:1 ethyl acetate/hexane)gave the product as a white solid (3.03 g, 75%). ¹H-NMR (CDCl₃) δ (1H,d), 7.98 (2H, m), 7.77 (1H, m), 7.68 (1H, d), 7.15 (2H, t), 4.77 (2H,d), 1.802 (1H, t); MS(APCI+) found (M+1)=204, C₁₂H₁₀FNO requires 203.

Intermediate A9—5-Formyl-2-(4fluorophenyl)pyridine

Activated manganese dioxide (3.19 g) was added to a solution ofIntermediate A8 (0.75 g) in dichloromethane (50 ml) and stirred at roomtemperature for 16 h. The solids were filtered off and the filtrateevaporated to a pale yellow solid (0.57 g). ¹H-NMR (CDCl₃) δ 10.15 (1H,s), 9.11 (1H, s), 8.22 (1H, dd), 8.10 (2H, m), 7.87 (1H, d), 7.20 (2H,t); MS(APCI+) found (M+1)=202, C₁₂H₈FNO requires 201.

Intermediate A10—N-Methyl-4-(4-chlorophenyl)-3-fluorobenzylamine

Borane (1M solution in THF, 2 equiv) was stirred under argon with icecooling, and a suspension of Intermediate A39 (1 equiv) in dry THF wasadded gradually over a few minutes. After 5 mins the ice bath wasremoved and the mixture heated to reflux for 1 h, then cooled to roomtemperature. 5M Hydrochloric acid was added dropwise, and the THF wasremoved from the resulting suspension by distillation. The residue wasdiluted with water and made strongly basic with sodium hydroxide, thenthe product was extracted into ether. Drying and evaporation of theorganic solution, followed by chromatography gave the title compound asan oil (88%). ¹H-NMR (CDCl₃) δ 2.48 (3H, s), 3.79(2H, s), 7.12–7.18 (2H,m), 7.33–7.50 (5H, m); MS (APCI+) found (M+1)=250; C₁₄H₁₃ClFN requires249.

Intermediate A11—N-(Ethoxycarbonylmethyl)-4-(4-chlorophenyl)benzylamine

A mixture of Intermediate A1 (0.5 g, 1 equiv), glycine ethyl esterhydrochloride (0.32 g, 1 equiv), diisopropylethylamine (0.4 ml, 1 equiv)and 1,2-dichloroethane (10 ml) was stirred at room temperature, sodiumtriacetoxyborohydride (0.73 g, 1.5 equiv) was added, and stirringcontinued overnight. After diluting with dichloromethane, the solutionwas washed with water and dried over potassium carbonate. Evaporation ofthe solvent yielded the title compound (0.57 g) as a white waxy solid.¹H-NMR (CDCl₃) δ 1.22–1.37 (3H, t), 3.44 (2H, s), 3.85 (2H, s),4.15–4.32 (2H, q), 7.35–7.62 (8H, m); ); MS (APCI+) found (M+1)=304;C₁₇H₁₈ClNO₂ requires 303.

Intermediate A12—2-Hydroxymethyl-5-(4-chlorophenyl)pyridine

m-Chloroperbenzoic acid (0.93 g) was added portionwise over 30 min to asolution of Intermediate A41 (0.77 g) in dichloromethane (10 ml), thenthe mixture was stirred at room temperature for a further hour, dilutedwith dichloromethane, washed with aq. sodium bicarbonate, dried andevaporated. Chromatography (silica, 5% methanol in dichloromethane) gave2-methyl-5-(4-chlorophenyl)pyridine-N-oxide (0.79 g) as a white solid.This material was dissolved in dichloromethane (15 ml), trifluoroaceticanhydride (1.9 ml) added, and the mixture stirred for 1 hour at roomtemperature followed by 1 hour at reflux. Volatile components wereremoved in vacuo, then the residue was redissolved in dichloromethane (5ml), 2M aq. sodium carbonate (14 ml) was added, and stirred vigorouslyfor 2 hours. The mixture was diluted with dichloromethane and water, andthe organic layer was washed with water, dried and evaporated.Chromatography (silica, 5% methanol in dichloromethane) gave the titlecompound (0.67 g) as an off-white solid. ¹H-NMR (CDCl₃) δ 3.61 (1H,t),4.82 (2H,d), 7.33 (1H,d), 7.45 (2H,m), 7.51 (2H,m), 7.85 (1H,dd), 7.78(1H,d); MS (APCI+) found (M+1)=220/222; C₁₂H₁₀ClNO requires 219/221.

Intermediate A13—Ethyl 2-(4-chlorophenyl)-4-oxopyrimidine-5-carboxylate

Sodium ethoxide (11.12 ml, 2 equiv) as a 21% w/v solution in ethanol wasadded dropwise to a suspension of diethyl ethoxymalonate (3.03 ml, 1equiv) and 4-chlorobenzamidine hydrochloride (4.23 g, 1 equiv) inethanol (30 ml), then the mixture was heated to reflux for 4 hours.After cooling, the solvent was removed in vacuo and the residue wastriturated with ether. The solid was filtered off, then resuspended inwater and acidified to pH 2. The product was filtered off, washed withwater and dried; yield 2.94 g. ¹H-NMR (d₆-DMSO) δ 1.29 (3H,t), 4.26(2H,q), 7.65 (2H,m), 8.18 (2H,m), 8.65 (1H,s); MS (APCI−) found(M−1)=277/279; C₁₃H₁₁ClN₂O₃ requires 278/280.

Intermediate A14—Ethyl2-(4-chlorophenyl)-4-chloropyrimidine-5-carboxylate

Oxalyl chloride (0.31 ml, 2 equiv) was added to Intermediate A13 (0.49g) in dichloromethane (20 ml) with ice cooling, then the mixture wasstirred for 3 hours with warming to room temperature. Evaporation of thevolatile components gave the product as a white solid (2.94 g). ¹H-NMR(CDCl₃) δ 1.44 (3H,t), 4.48 (2H,q), 7.50 (2H,m), 8.45 (2H,m), 9.17(1H,s); MS (APCI+) found (M+1)=297; C₁₃H₁₀Cl₂N₂O₂ requires 296.

Intermediate A15—Ethyl 2-(4-chlorophenyl)pyrimidine-5-carboxylate

A mixture of Intermediate A14 (6.8 g, 1 equiv), zinc powder (1.79 g, 1.2equiv), acetic acid (1.57 ml, 1.2 equiv) and THF (100 ml) was stirred at60° C. under argon for 18 hours, then a further portion of acetic acid(1 ml) and zinc (1.0 g) was added, and the reaction allowed to continuefor a further 24 hours. The solvent was removed in vacuo, the residuewas taken up in a mixture of dichloromethane and methanol, andundissolved zinc powder was removed by filtration. After evaporation ofthe solvent, the product crystallised from ethanol; yield 2.02 g. ¹H-NMR(CDCl₃) δ 1.44 (3H,t), 4.46 (2H,q), 7.48 (2H,m), 8.48 (2H,m), 9.30(2H,s); MS (APCI+) found (M+1)=263; C₁₃H₁₁ClN₂O₂ requires 262.

Intermediate A16—5-Hydroxymethyl-2-(4-trifluoromethylphenyl)pyrimidine

Intermediate A129 (0.96 g) was hydrogenated over 10% palladium oncharcoal (96 mg) in a mixture of triethylamine (2 ml) and ethanol (20ml) for 90 mins at 1 atmosphere pressure. The catalyst was removed byfiltration, the solvent was evaporated, and the residue was taken up inethyl acetate and washed successively with aq. ammonium chloride and aq.sodium bicarbonate. Drying and evaporation gave the title compound (2.02g). ¹H-NMR (CDCl₃) δ 4.82 (2H,s), 7.75 (2H,m), 8.57 (2H,m), 8.85 (2H,s);MS (APCI+) found (M+1)=255; C₁₁H₉ClN₂O requires 254.

The following intermediates were made by the method of Intermediate A1:

No. Precursors Structure Name A20 4-formylboronicacid,4-fluoroiodobenzene

4-(4-Fluorophenyl)benzaldehyde A212-bromothiophene-5-carboxaldehyde,4-fluorobenzeneboronic acid

5-(4-Fluorophenyl)-2-thiophenecarboxaldehyde A222-bromothiophene-5-carboxaldehyde,4-chlorobenzeneboronic acid

5-(4-Chlorophenyl)-2-thiophenecarboxaldehyde A23 methyl6-chloronicotinate,4-fluorobenzeneboronic acid

Methyl 6-(4-fluorophenyl)-nicotinate A24 methyl6-chloronicotinate,4-chlorobenzeneboronic acid

Methyl-6-(3,4-dichlorophenyl)-nicotinate A25 methyl6-chloronicotinate,3,4-dichlorobenzeneboronicacid

Methyl-6-(3,4-dichlorophenyl)-nicotinate A264-bromobenzaldehyde,4-trifluoromethylbenzene-boronic acid

4-(4-Trifluoromethylphenyl)-benzaldehyde A274-bromo-2-fluorobenzaldehyde,4-chlorobenzeneboronic acid

4-(4-Chlorophenyl)-2-fluoro-benzaldehyde A28 4-formylbenzeneboronicacid,4-chloro-2-fluoroiodobenzene

4-(4-Chloro-2-fluorophenyl)-benzaldehyde A29 4-formylbenzeneboronicacid,4-chloro-3-fluoroiodobenzene

4-Chloro-3-fluorophenyl)-benzaldehyde A30 4-methoxybenzeneboronicacid,4-bromobenzaldehyde

4-(4-Methoxyphenyl)-benzylaldehyde A31 4-formylbenzeneboronicacid,4-chloro-2-fluoroiodobenzene

4-(2-Fluoro-4-chlorophenyl)-benzaldehyde A32 4-formylbenzeneboronicacid,2,4-bis(trifluoromethyl)-bromobenzene

4-(2,4-bis(trifluoromethyl)-phenyl)benzaldehyde A334-formylbenzeneboronic acid,4-bromo-3-fluorobenzo-trifluoride

4-(2-Fluoro-4-trifluoromethyl-phenyl)benzaldehyde A344-bromo-2-fluorobenzaldehyde,4-trifluoromethylbenzene-boronic acid

2-Fluoro-4-(4-trifluoromethyl-phenyl)benzaldehyde A353-chloro-4-fluorobenzene-boronic acid,4-bromobenzaldehyde

3-Chloro-4-fluorophenyl)-benzaldehyde A36 4-formylbenzeneboronicacid,2,4-difluoroiodobenzene

4-(2,4-Difluorophenyl)-benzaldehyde A37 4-formylbenzeneboronicacid,4-trifluoromethoxyiodobenzene

4-(4-Trifluoromethoxyphenyl)-benzaldehyde A38 4-formylbenzeneboronicacid,4-difluoromethoxyiodobenzene

4-(4-Difluoromethoxyphenyl)-benzaldehyde A39N-methyl-4-bromo-3-fluorobenzamide,4-chlorobenzeneboronic acid

N-Methyl-4-(4-chlorophenyl)-3-fluorobenzamide A40 methyl6-chloronicotinate,4-trifluoromethylbenzeneboronic acid

Methyl 6-(4-trifluoromethyl-phenyl)nicotinate A412-methyl-5-bromopyridine,4-chlorobenzeneboronic acid

2-methyl-5-(4-trifluoromethyl-phenyl)pyridine A422-methyl-5-triflylpyridine,4-trifluoromethylbenzeneboronicacid

2-methyl-5-(4-trifluoromethyl-phenyl)pyridine A432-methyl-5-triflylpyridine,4-trifluoromethoxybenzene-boronic acid

2-methyl-5-(4-trifluoromethoxy-phenyl)pyridine

The following intermediates were made by the method of Intermediate A2,using an appropriate amine in place of methylamine as necessary:

No. Precursor Structure Name A44 Int. A20

N-Methyl-4-(4-fluorophenyl)benzylamine A45 Int. A26

N-Methyl-4-(4-trifluoromethylphenyl)-benzylamine A46 Int. A27

N-Methyl-4-(4-chlorophenyl)-2-fluoro-benzylamine A47 Int. A28

N-Methyl-4-(4-chloro-2-fluorophenyl)-benzylamine A48 Int. A1

N-Ethyl-4-(4-chlorophenyl)benzylamine A49 Int. A131

5-Methylaminomethyl-2-(3,4-dichlorophenyl)-pyridine A50 Int. A1

N-(Dimethylaminocarbonylmethyl)-4-(4-chlorophenyl)benzylamine A51 Int.A1

N-(2-Methoxyethyl)-4-(4-chlorophenyl)-benzylamine A52 Int. A26

N-(Dimethylaminocarbonylmethyl)-4-(4-trifluoromethylphenyl)benzylamineA53 Int. A29

N-Methyl-4-(4-chloro-3-fluorophenyl)-benzylamine A54 Int. 30

N-Methyl-4-(4-methoxyphenyl)benzylamine A55 Int. A31

N-Methyl-4-(2-fluoro-4-chlorophenyl)-benzylamine A56 Int. A32

N-Methyl-4-(2,4-bis(trifluoromethyl)phenyl)-benzylamine A57 Int. A33

N-Methyl-4-(2-fluoro-4-trifluorormethylphenyl)-benzylamine A58 Int. A34

N-Methyl-2-fluoro-4-(4-trifluoromethyl-phenyl)benzylamine A59 Int. A35

N-Methyl-4-(3-chloro-4-fluorophenyl)-benzylamine A60 Int. A36

N-Methyl-4-(2,4-difluorophenyl)benzylamine A61 Int. A1

N-(2-Dimethylaminoethyl)-4-(4-chlorophenyl)-benzylamine A62 Int. A1

N-(3-Dimethylaminopropyl)-4-(4-chlorophenyl)-benzylamine A63 Int. A21

2-Methylaminomethyl-5-(4-fluorophenyl)-thiophene A64 Int. A9

5-Methylaminomethyl-2-(4-fluorophenyl)-pyridine A65 Int. A130

5-Methylaminomethyl-2-(4-chlorophenyl)-pyridine A66 Int. A22

2-Methylaminomethyl-5-(4-chlorophenyl)-thiophene

A67: N-Methyl-4-phenylbenzylamine was made from commercially available4-biphenylcarboxaldehyde.

The following intermediates were made by the method of Intermediate A3:

No. Precursor Structure Name A70 Int. A1

N-(2-Hydroxyethyl)-4-(4-chlorophenyl)-benzylamine A71 Int. A26

N-(2-Hydroxyethyl)-4-(4-trifluoromethylphenyl)benzylamine A72 Int. A26

N-(2-(dimethylamino)ethyl)-4-(4-trifluoromethylphenyl)benzylamine A73Int. A26

N-(2-(diethylamino)ethyl)-4-(4-trifluoro-methylphenyl)benzylamine A74Int. A1

N-(2-(diisopropylamino)ethyl)-4-(4-chlorophenyl)benzylamine A75 Int. A1

N-(2-(1-pyrrolidino)ethyl)-4-(4-chloro-phenyl)benzylamine A76 Int. A1

N-(2-(4-morpholino)ethyl)-4-(4-chloro-phenyl)benzylamine A77 Int. A1

N-(2-(4-methyl-1-piperazino)ethyl)-4-(4-chlorophenyl)benzylamine A78Int. A26

N-(3-(dimethylamino)propyl)-4-(4-trifluoromethylphenyl)benzylamine A79Int. A1

N-(3-diethylamino)propyl)-4-(4-chloro-phenyl)benzylamine A80 Int. A1

N-(3-(1-pyrrolidino)propyl)-4-(4-chloro-phenyl)benzylamine A81 Int. A1

N-(3-(1-piperidino)propyl)-4-(4-chloro-phenyl)benzylamine A82 Int. A1

N-(3-(4-morpholino)propyl)-4-(4-chloro-phenyl)benzylamine A83 Int. A1

N-(3-(4-methyl-1-piperazino)propyl)-4-(4-chlorophenyl)benzylamine A84Int. A1

N-(2-(t-butoxycarbonylamino)ethyl)-4-(4-chlorophenyl)benzylamine A85Int. A1

N-(N′-(2-(t-butoxycarbonyl)-N′-methyl-amino)ethyl)-4-(4-chlorophenyl)-benzylamineA86 Int. A1

N-(N′-(2-(t-butoxycarbonyl)-N′-ethyl-amino)ethyl)-4-(4-chlorophenyl)-benzylamineA87 Int. A26

N-(N′-(2-(t-butoxycarbonyl)-N′-ethyl-amino)ethyl)-4-(4-trifluoromethyl-phenyl)benzylamineA88 Int. A1

N-(3-(t-butoxycarbonylamino)propyl)-4-(4-chlorophenyl)benzylamine A89Int. A1

N-(N′-(3-(t-butoxycarbonyl)-N′-methyl-amino)propyl)-4-(4-trifluoromethyl-phenyl)benzylamineA90 Int. A1

N-(2-(4-t-butoxycarbonyl-1-piperazino)-ethyl)-4-(4-chlorophenyl)benzylamineA91 Int. A1

N-(2-(2-oxo-4-t-butoxycarbonyl-1-piperazino)ethyl)-4-(4-chlorophenyl)-benzylamineA92 Int. A37

N-(2-diethylamino)ethyl)-4-(4-trifluoro-methoxyphenyl)benzylamine A93Int. A38

N-(2-(diethylamino)ethyl)-4-(4-difluoro-methoxyphenyl)benzylamine A94Int. A1

N-(2-(N′-(2-hydroxyethyl)-N′-ethyl-amino)ethyl)-4-(4-chlorophenyl)-benzylamineA95 Int. A1

N-(2-(bis-(2-hydroxyethyl)amino)ethyl)-4-(4-chlorophenyl)benzylamine A96Int. A26

N-((4-morpholino)carbonylmethyl)-4-(4-trifluoromethylphenyl)benzylamineA97 Int. A26

N-((4-methyl-1-piperazino)carbonyl-methyl)-4-(4-trifluoromethylphenyl)-benzylamineA98 Int. A133

N-(2-(diethylamino)ethyl)-5-(4-chloro-phenyl)pyrid-2-ylmethylamine A99Int. A134

N-(2-(diethylamino)ethyl)-5-(4-trifluoro-methylphenyl)pyrid-2-ylmethylamineA100 Int. A132

N-(2-(dimethylamino)ethyl)-2-(4-trifluoromethylphenyl)pyrid-5-yl-methylamineA101 Int. A130

N-(2-(diethylamino)ethyl)-2-(4-chloro-phenyl)pyrid-5-ylmethylamine A102Int. A135

N-methyl-5-(4-trifluoromethoxyphenyl)-pyrid-2-ylmethylamine A103 Int.A130

N-(2-hydroxyethyl)-2-(4-chlorophenyl)-pyrid-5-ylmethylamine A104 Int.A136

N-(2-(diethylamino)ethyl)-2-(4-chloro-phenyl)pyrimid-5-ylmethylamineA105 Int. A137

N-(2-(diethylamino)ethyl)-2-(4-trifluoro-methylphenyl)pyrimid-5-ylmethylamineA106 Int. A132

N-(2-(diethylamino)ethyl)-2-(4-trifluoro-methylphenyl)pyrid-5-ylmethylamineA107 Int. A1

N-(2-(1-piperidino)ethyl)-4-(4-chloro-phenyl)benzylamine A108 Int. A26

N-(2-(1-piperadino)ethyl)-4-(4-trifluoro-methylphenyl)benzylamine

The following intermediates were made by the method of Intermediate A4:

No. Precursor Structure Name A110 Int. A20

4-(4-Fluorophenyl)benzyl alcohol A111 Int. A26

4-(4-Trifluoromethylphenyl)benzyl alcohol A112 Int. A22

5-Hydroxymethyl-2-(4-chlorophenyl)thiophene

The following intermediates were made by the method of Intermediate A5:

No. Precursor Structure Name A115 Int. A110

N-(4-(4-Fluorophenyl)benzyl)phthalimide A116 Int. A111

N-(4-(4-Trifluoromethylphenyl)benzyl)-phthalimide A117 Int. A8

N-(2-(4-Fluorophenyl)pyrid-5-ylmethyl)-phthalimide A118 Int. A112

N-(5-(4-Chlorophenyl)thien-2-ylmethyl)-phthalimide

The following intermediates were made by the method of Intermediate A6:

No. Precursor Structure Name A120 Int. A115

4-(4-Fluorophenyl)benzylamine A121 Int. A116

4-(4-Trifluoromethylphenyl)benzylamine A122 Int. A117

5-Aminomethyl-2-(4-fluorophenyl)pyridine A123 Int. A118

5-Aminomethyl-2-(4-chlorophenyl)thiophene

A124: 4-Phenylbenzylamine is commercially available.

The following intermediates were made by the method of Intermediate A8:

No. Precursor Structure Name A125 Int. A24

5-Hydroxymethyl-2-(4-chlorophenyl)pyridine A126 Int. A25

5-Hydroxymethyl-2-(3,4-dichlorophenyl)pyridine A127 Int. A40

5-Hydroxymethyl-2-(4-trifluoromethylphenyl)-pyridine A128 Int. A15

5-Hydroxymethyl-2-(4-chlorophenyl)pyrimidine A129 Int. A150

4-chloro-5-hydroxymethyl-2-(4-trifluoromethyl-phenyl)pyrimidine

The following intermediates were made by the method of Intermediate A9:

No. Precursor Structure Name A130 Int. A125

5-Formyl-2-(4-chlorophenyl)pyridine A131 Int. A126

5-Formyl-2-(3,4-dichlorophenyl)pyridine A132 Int. A127

5-Formyl-2-(4-trifluoromethylphenyl)pyridine A133 Int. A12

2-Formyl-5-(4-chlorophenyl)pyridine A134 Int. A140

2-Formyl-5-(4-trifluoromethylphenyl)pyridine A135 Int. A141

2-Formyl-5-(4-trifluoromethoxyphenyl)pyridine A136 Int. A128

5-Formyl-2-(4-chlorophenyl)pyrimidine A137 Int. A16

5-Formyl-2-(4-trifluoromethylphenyl)pyrimidine

The following intermediates were made by the method of Intermediate A12:

No. Precursor Structure Name A140 Int. A134

2-hydroxymethyl-5-(4-trifluoromethylphenyl)-pyridine A141 Int. A135

2-hydroxymethyl-5-(4-trifluoromethoxyphenyl)-pyridine

The following intermediate was made by the method of Intermediate A13:

No. Precursors Structure Name A145 diethylethoxymalonate,4-trifluoromethyl-benzamidine.HCl

Ethyl 2-(4-trifluoromethylphenyl)-4-oxopyrimidine-5-carboxylate

The following intermediate was made by the method of Intermediate A14:

No. Precursor Structure Name A150 Int. A145

Ethyl 2-(4-trifluoromethylphenyl)-4-chloro-pyrimidine-5-carboxylate

The following intermediate was made by the method of Intermediate A7:

No. Precursor Structure Name A155 Int. A45

N-Methyl-N-(4-(4-trifluoromethylphenyl)-benzyl)bromoacetamide

The following intermediate was made by the method of Intermediate A11:

No. Precursor Structure Name A160 Int. A26

N-(Ethoxycarbonylmethyl)4-(4-trifluoromethyl-phenyl)benzylamineIntermediate B1—Ethyl 2-trifluoromethyl-4-oxopyrimidine-5-carboxylate

To a solution of trifluoroacetamidine (36.5 g) and diethylethoxymalonate (71 g) in ethanol (300 ml) was added a solution of sodiumethoxide in ethanol (21 wt %, 109.5 ml) over 5 min. The mixture washeated at reflux for 6 h, then cooled, concentrated and water (200 ml)added. The resulting solid was collected by filtration, washed with coldwater (50 ml) and diethyl ether (2×100 ml) and then suspended in water(400 ml). Dichloromethane (300 ml) was added and the mixture acidifiedwith dilute HCl (2.5 M, 125 ml). The organic extract was washed withwater, dried (MgSO₄) and evaporated to give the tide compound as a buffsolid (53 g, 68%). ¹H-NMR (CDCl₃) δ 12.00 (1H, br s), 9.18 (1H, s), 4.57(2H, q), 1.49 (3H, t); ¹³C-NMR (CDCl₃) δ 171.4, 167.3, 160.4, 160.2 (q,J=38 Hz), 118.8 (q, J=276 Hz), 109.2, 63.8, 14.0; MS (APCI+) found(M+1)=237, C₈H₇F₃N₂O₃ requires 236.

Intermediate B2—Ethyl 2-trifluoromethyl-4-chloropyrimidine-5-carboxylate

To a solution of ethyl4-hydroxy-2-trifluorormethylpyrimidine-5-carboxylate (51.8 g) indichloromethane (600 ml) cooled in an ice bath was added oxalyl chloride(57.4 ml) followed by dimethylformamide (0.2 ml). The mixture was stirat room temperature for 16 h and then evaporated. Toluene was added andevaporated. The residue was dissolved in dichloromethane, washed withwater, dried (MgSO₄) and evaporated to give the title compound as anorange oil (55.7 g, 100%). ¹H-NMR (CDCl₃) δ 9.25 (1H, s), 4.51 (2H, q),1.46 (3H, t); ¹³C-NMR (CDCl₃) δ 126.0 (2C), 161.1, 158.1 (q, J=39 Hz),127.0, 118.9 (q, J=276 Hz), 63.5, 14.4.

Intermediate B3—Ethyl 2-trifluorormethylpyrimidine-5-carboxylate

A mixture of ethyl 4-chloro-2-trifluoromethylpyrimidine-5-carboxylate(55.7 g), 10% palladium on carbon (0.3 g), ethanol (1000 ml) andN,N-diisopropylethylamine (90 ml) was shaken under hydrogen pressuremaintained at 1 atmosphere for 2 h. The catalyst was then filtered offand the solvents evaporated. The residue was dissolved indichloromethane, washed with ammonium chloride solution, then water,dried (MgSO₄) and evaporated to give the title compound as a buff solid(48 g, 100%). ¹H-NMR (CDCl₃) δ 9.42 (2H, s), 4.51 (2H, q), 1.45 (3H, t);¹³C-NMR (CDCl₃) δ 162.7, 159.4 (2C), 159.3 (q, J=37 Hz), 126.3, 119.6(q, J=275 Hz), 62.9, 14.4.

Intermediate B4—2-Trifluoromethyl-5-formylpyrimidine

To a solution of ethyl 2-trifluoromethylpyrimidine-5-carboxylate (5.17g) in toluene (120 ml) cooled in dry ice/acetone was added a solution ofdiisobutylaluminium hydride (25 wt %, 31 ml) over 15 min. The mixturewas stirred at −78° C. for 45 min, then dilute HCl (2M, 120 ml) wasadded cautiously. After allowing the mixture to warm to room temperaturediethyl ether was added. The organic phase was separated, washed withwater, then brine, dried (MgSO₄) and evaporated to give the titlecompound as a colourless solid (3.46 g, 84%). ¹H-NMR (CDCl₃) δ 10.29(1H, s), 9.37 (2H, s); ¹³C-NMR (CDCl₃) δ 187.7, 159.6 (q, J=38 Hz),159.1 (2C) 129.6, 119.2 (q, J=276 Hz).

Intermediate B5—1-(2-Methoxyethyl)pyrazole

2-Bromomethyl methyl ether (10.22 g) was added dropwise with stirring toa mixture of pyrazole (5.0 g), finely powdered potassium hydroxide (8.25g) and tetrabutylammonium bromide (1.19 g) with occasional ice coolingto keep the temperature below 10° C. The mixture was allowed to stand atroom temperature for 48 hours, then columned on silica and eluted withether. Product fractions were evaporated to a pale green oil (7.27 g).¹H-NMR (CDCl₃) δ 3.33 (3H,s), 3.75 (2H,t), 4.30 (2H,t), 6.25 (1H,s),7.47 (1H,d), 7.52 (1H,d); MS (APCI+) found (M+H)=127; C₆H₁₀N₂O requires126.

Intermediate B6—1-(2-Methoxyethyl)pyrazole carboxaldehyde

A solution of 1-(2-methoxyethyl)pyrazole (7.27 g) in dry DMF (11.4 ml)was heated to 90° C., then phosphorus oxychloride (5.4 ml) was addeddropwise over 1 hour, maintaining the temperature between 95–100° C.After heating for a further 2 hours, the mixture was cooled and pouredonto ice. Sodium hydroxide was added to adjust the mixture to pH 4, thenthe product was extracted into dichloromethane. Drying and evaporationof the organic extracts yielded a brown oil (7.19 g). ¹H-NMR (CDCl₃) δ3.34 (3H,s), 3.75 (2H,m), 4.32 (2H,m), 7.98 (1H,s), 8.02 (1H,s), 9.85(1H,s).

Intermediate B10—3-(1-Methylpyrazol-4-yl)acrylic acid

A mixture of 1-methylpyrazole-4-carboxaldehyde (85.55 g), malonic acid(80.85 g), pyridine (69.2 ml) and piperidine (1.5 ml) was heated to 110°C. under argon for 4 hours. After cooling, water (100 ml) was added,followed by aqueous ammonia (75 ml) to obtain a clear solution, whichwas acidified to pH1 with hydrochloric acid. The resulting solid wasfiltered off, washed with water and dried to obtain the tide compound(93.5 g). ¹H-NMR (d₆-DMSO) δ 3.83 (3H,s), 6.18 (1H,d), 7.44 (1H,d), 7.83(1H,s), 8.07 (1H,s). (APCI) found (M+H)=153. C₇H₈N₂O₂ requires 152.

Intermediate B11—Methyl 3-(1-methylpyrazol-4-yl)acrylate

3-(1-Methylpyrazol-4-yl)acrylic acid (86.8 g) was added to a solution ofsulphuric acid (20 ml) in methanol (690 ml), and the mixture refluxedfor 2.5 hours, cooled, then poured onto ice. The acid was neutralisedwith aqueous sodium hydroxide and the product extracted intodichloromethane, which was dried and evaporated. Crystallisation fromether/petrol gave methyl 3-(1-methylpyrazol-4-yl)acrylate (89.0 g).¹H-NMR (d₆-DMSO) δ 3.77 (3H,s), 3.91 (3H,s), 6.16 (1H,d), 7.54 (1H,s),7.56 (1H,d), 7.69 (1H,s). (APCI) found (M+H)=167. C₈H₁₀N₂O₂ requires166.

Intermediate B12—Ethyl 3-(5-pyrimidinyl)acrylate

A mixture of 5-bromopyrimidine (5.93 g), ethyl acrylate (5.08 g),palladium acetate (0.112 g), triphenyl phosphine (0.23 g) andtriethylamine (4.5 g) was stirred at 150° C. in a pressure vessel for 6hours. After cooling overnight, water (50 ml) was added to the darkresidue, and the product was extracted into toluene. Drying, charcoalingand evaporation gave a pale oil, which was triturated with pet ether toobtain ethyl 3-(5-pyrimidyl)acrylate (4.78 g). ¹H-NMR (CDCl₃) δ 1.36(3H,t), 4.27 (2H,q), 6.59 (1H,d), 7.62 (1H,d), 8.88 (2H,s), 9.20 (1H,s).

Intermediate B13—Ethyl 3-(2-methoxypyrimidin-5-yl)acrylate

A mixture of 2-methoxy-5-bromopyrimidine (75.43 g, 0.399 mol), ethylacrylate (47.5 ml, 0.439 mol), palladium (II) acetate (1.07 g, 0.0048mol), tri-o-tolylphosphine (2.92 g, 0.0096 mol) and triethylamine (84ml) were heated at 135° C. (oil bath temperature) with stirring underargon for 12 h. After allowing to cool the solid mass was dissolved inwater and ethyl acetate, filtered, and the aqueous phase separated andfurther extracted with ethyl acetate. The combined extracts were washedwith saturated aqueous ammonium chloride, dried (MgSO₄) and evaporated.The solid thus obtained was triturated with ether/light petrol (1:3, 350ml), filtered, washed and dried, yield 52.41 g (63%). ¹H-NMR (CDCl₃) δ1.33 (3H, t), 4.06 (3H, s), 4.28 (2H, q), 6.45 (1H, d), 7.58 (1H, d),8.67 (2H, s); MS (APCI+) found (M+H)=209; C₁₀H₁₂N₂O₃ requires 208.

The following intermediates were prepared by the method of intermediateB10 (Knoevenagel):

No. Precursors Structure Name B14 Int. B4

3-(2-Trifluoromethylpyrimidin-5-yl)acrylic acid B15 Int. B6

3-(1-(2-Methoxyethyl)pyrazol-4-yl)acrylic acid

The following intermediates were prepared by the method of intermediateB11 (esterification):

No. Precursors Structure Name B16 Int. B14

Methyl 3-(2-trifluoromethylpyrimidin-5-yl)acrylate B17 Int. B15

Methyl 3-(1-(2-methoxyethyl)pyrazol-4-yl)acrylate

The following intermediates were prepared by the method of intermediateB13 (acrylate Heck):

No. Precursors Structure Name B18 2-dimethylamino-5-bromopyrimidine

Ethyl 3-(2-dimethylamino-5-pyrimidyl)-acrylate B192-(4-morpholino)-5-bromopyrimidine

Ethyl 3-[2-(4-morpholino)-5-pyrimidyl]-acrylateIntermediate B20—Methyl 3-(1-methylpyrazol-4-yl)propionate

A solution of methyl 3-(1-methylpyrazol-4-yl)acrylate (181 g) inmethanol (2 litres) was hydrogenated over 10% palladium on charcoal (5.2g) at 50° C./50 psi until uptake ceased. The catalyst was filtered off,the methanol was removed in vacuo, finally by azeotroping with toluene.The title compound was obtained as an oil (179 g). ¹H-NMR (d₆-DMSO) δ2.56 (2H,t), 2.79 (2H,t), 3.67 (3H,s), 3.85 (3H,s), 7.17 (1H,s), 7.31(3H,s). (APCI) M+H=169. C₈H₁₂N₂O₂ requires 168.

Intermediate B21—Ethyl 3-(2-methoxypyrimidin-5-yl)propanoate

A suspension of ethyl 3-(2-methoxypyrimidin-5-yl)acrylate (52.4 g, 0.252mol) in ethanol (400 ml) and triethylamine (50 ml) was treated with 10%palladium on carbon (3 g) and hydrogenated at 50 psi for 1.75 h. Thecatalyst was filtered off through hyflo and the filtrate evaporated. Theresidue was dissolved in dichloromethane, washed twice with saturatedaqueous ammonium chloride, dried (MgSO₄) and evaporated to an oil, yield41.2 g (78%). ¹H-NMR (CDCl₃) δ 1.23 (3H, t), 2.61 (2H, t), 2.87 (2H, t),3.99 (3H, s), 4.13 (2H, q), 8.39 (2H, s); MS (APCI+) found (M+H)=211;C₁₀H₁₄N₂O₃ requires 210.

The following intermediates were made by the method of Intermediate B20(ethyl esters in ethanol solvent, methyl esters in methanol):

No. Precursors Structure Name B22 Int. B12

Ethyl 3-(5-pyrimidyl)propionate B23 Int. B17

Methyl 3-(1-(2-methoxyethyl)pyrazol-4-yl)propionate

The following intermediates were made by the method of Intermediate B21(ethyl esters in ethanol solvent, methyl esters in methanol):

No. Precursors Structure Name B24 Int. B16

Methyl 3-(2-trifluoromethylpyrimidin-5-yl)-propanoate B25 Int. B18

Ethyl 3-(2-dimethylamino-5-pyrimidyl)propionate B26 Int. B19

Ethyl 3-[2-(4-morpholino)-5-pyrimidyl]propionateIntermediate B30—5-((1-Methylpyrazol-4-yl)methyl)-2-thiouracil

A solution of methyl 3-(1-methylpyrazol-4-yl)propionate (170 g) andmethyl formate (131 ml) in dry diethyl ether (2000 ml) was addeddropwise over 2 hours to a stirred, ice-cooled solution of potassiumtert-butoxide (284 g) in dry THF (1800 ml) under argon. The mixture wasthen allowed to warm to room temperature and stirring continued for 16hours. The solvents were evaporated in vacuo to a pale solid. Methanol(2500 ml) and thiourea (154 g) were added, and the mixture was heated to50° C. for 16 hours with vigorous stirring. The solvent was evaporated,and the pale brown solid residue was taken up in water (750 ml). Theice-cooled solution was adjusted to pH3 with hydrochloric acid, stirredfor 2 hours in the ice bath, then the precipitat was filtered off andwashed with water and ether to obtain the title compound (120 g). ¹H-NMR(d₆-DMSO) δ 3.33 (3H,s), 3.75 (3H,s), 7.15 (1H,s), 7.23 (1H,s), 7.46(1H,s), 12.2 (1H,br s), 12.4 (1H,br s). (APCI) M+H=223. C₉H₁₀N₄OSrequires 222.

Intermediate B31—Ethyl 2-formyl-3-(5-pyrimidyl)propionate

A mixture of ethyl 3-(5-pyrimidyl)propionate (2.28 g) and ethyl formate(1.41 ml) dissolved in dry dimethoxyethane (5 ml) was added dropwiseover 30 min to a suspension of sodium hydride (60%, 4.0 g) in DME (5 ml)under nitrogen, keeping the temperature below 0° C. Stirring wascontinued for a further 24 h, then the mixture was poured onto ice andwashed with ether. The aqueous layer was adjusted to pH 7, thenevaporated and the residue extracted with acetone. Filtration andevaporation gave crude product, which was taken up in ethyl acetate,charcoaled, dried and evaporated to give ethyl2-formyl-3-5-pyrimidyl)propionate. Like other compounds of this type,this proved difficult to characterise and was used without furtherpurification.

Intermediate B32—5-(Pyrimid-5-ylmethyl)-2-thiouracil

Sodium (0.25 g) was dissolved in ethanol (5 ml), thiourea (0.77 g)added, and the mixture stirred under reflux for 1 hour. A solution ofethyl 2-formyl-3-(5-pyrimidyl)propionate (1.99 g) in ethanol (5 ml) wasadded slowly, and reflux continued for 18 hours. The solvent wasevaporated, and the residue taken up in water and washed withdichloromethane. The aqueous solution was acidified to pH 5, and theprecipitate filtered off, washed with water and dried to obtain5-pyrimid-5-ylmethyl)-2-thiouracil (0.71 g). ¹H-NMR (d6-DMSO) δ 3.58(2H,s), 7.54 (1H,s), 8.70 (2H,s) and 9.02 (1H,s). MPt 265–6° C.

The following intermediates were made by the method of Intermediate B30(thiouracils):

No. Precursors Structure Name B33 Int. B21

5-(2-Methoxypyrimidin-5-ylmethyl)-2-thiouracil B34 Int. B24

5-(2-Trifluoromethylpyrimidin-5-ylmethyl)-2-thiouracil B35 Int. B26

5-(2-(4-Morpholino)pyrimid-5-ylmethyl)-2-thiouracil B36 Int. B25

5-(2-Dimethylaminopyrimid-5-ylmethyl)-2-thiouracil B37 Int. B23

5-((1-(2-Methoxyethyl)pyrazol-4-yl)methyl)-2-thiouracil B38 ethyl3-phenyl-propionate

5-Benzyl-2-thiouracil B39 ethyl 3-(4-chlorophenyl)-propionate

5-(4-Chlorobenzyl)-2-thiouracilIntermediateB40—2-(Methoxymethylene)-3-(2-methoxypyrimidin-5-yl)propionic acid,mixed methyl/ethyl esters

To a stirring suspension of sodium hydride (0.83 g of a 60% dispersionin oil) in anhydrous 1,2-dimethoxyethane (6 ml) was added dropwise asolution of methyl formate (1.54 ml) and ethyl3-(2-methoxypyrimid-5-yl)propionate (3.5 g) in anhydrous1,2-dimethoxyethane (6 ml) at such a rate as to maintain the reactiontemperature at 25–30° C. After 1 h, ether was added and the precipitatedoil allowed to settle. The solution was decanted off and replaced withfresh ether, and the oil slowly solidified. The solid2-(hydroxymethylene) derivative was filtered, washed with ether anddried, yield 3.8 g. A 1.33 g portion was suspended in dimethyl formamide(10 ml) together with anhydrous potassium carbonate (1.15 g), and asolution of dimethyl sulphate (0.48 ml) in dimethylformamide (10 ml) wasadded dropwise with stirring over 30 min. After 16 h the solvent wasevaporated and the residue treated with water and extracted with ethylacetate. The extracts were washed with water, dried (MgSO₄) andevaporated to give the product as an oil, yield 0.91 g. ¹H-NMR (CDCl₃) δ1.23 (3H, t), 3.46 (2H, s), 3.69 (3H, s, methyl ester), 3.88 (3H, s),3.97 (3H, s), 4.16 (2H, q), 7.39 (1H, s), 8.40 (2H, s). 3:2 ratio ofmethyl:ethyl esters. MS (APCI+) found (M+1)=253, 239 (ethyl and methylesters); C₁₂H₁₆N₂O₄ requires 252, C₁₁H₁₄N₂O₄ requires 238.

IntermediateB41—2-(Methoxymethylene)-3-(2-methoxypyrimidin-5-yl)propionic acid

A suspension of the mixed esters of Intermediate B40 (0.9 g) in 2Maqueous sodium hydroxide (3.6 ml) was stirred at ambient temperature for16 h to give a clear solution. This was diluted with water, extractedwith dichloromethane and evaporated to about half volume, then acidifiedto pH 3–4 (2M hydrochloric acid) when the product crystallised out. Thewhite solid was filtered, washed with ice-cold water and dried, yield0.46 g. ¹H-NMR (CDCl₃) δ 3.43 (2H, s), 3.91 (3H, s), 3.99 (3H, s,) 7.49(1H, s), 8.42 (2H, s); MS (APCI+) found (M+1)=225, C₁₀H₁₂N₂O₄ requires224.

IntermediateB42—1-(3-Ethoxycarbonylprop-1-yl)-5-(2-methoxypyrimid-5-ylmethyl)-2-thiouracil

Oxalyl chloride (3.94 ml, 2 equiv) was added over 5 min to a solution ofIntermediate B41 (5.0 g, 1 equiv) and DMF (1 drop) in drydichloromethane (50 ml), then the mixture was stirred under argon for 4h. The solvent was evaporated, and the residue twice taken up indichloromethane and re-evaporated to remove volatile impurities. Theacid chloride was dissolved in acetonitrile (100 ml) and treated withdry, powdered potassium thiocyanate (3.2 g, 1.5 equiv). The resultingsuspension was stirred under argon for 24 h, then evaporated to dryness.The residue was suspended in dry DMF (100 ml), cooled to 10° C., ethyl4-aminobutyrate hydrochloride (4.60 g, 1.25 equiv) and triethylamine(7.34 ml, 2.4 equiv) added, and the mixture stirred at room temperaturefor 20 h. Sodium methoxide solution (prepared by dissolving sodium (1.26g, 2.5 equiv) in methanol (25 ml)) was added to the DMF solution, andthe mixture heated to 110° C. for 2 h. The solvent was evaporated, waterwas added, and acidified to pH 5 with acetic acid, then the productextracted into ethyl acetate. Drying, evaporation, and trituration withether gave a pale brown solid (4.55 g). Some ether/ester exchange tookplace during the reaction, and the title compound was obtained mixedwith ca 30% of the corresponding 2-ethoxypyrimidine. ¹H-NMR (DMSO-d₆) δ1.17 (3H, t), 1.31 (t, ethoxy), 1.97 (2H, t), 2.36 (2H, t), 3.49 (s,ethoxy), 3.51 (s, methoxy), 3.88 (s, methoxy), 4.04 (2H, q), 4.16 (2H,t), 4.31 (q, ethoxy), 7.81 (1H, s), 8.48 (s, ethoxy), 850 (s, methoxy),12.50 (bs, NH) (light brown solid).

The following intermediates were prepared by the method of intermediateB40:

No. Precursor Structure Name B43 Int. B20

Methyl 2-(methoxymethylene)-3-(1-methylpyrazol-4-yl)propionate B44 Int.B26

Ethyl 2-(methoxymethylene)-3-(2-(4-morpholino)-pyrimidin-5-yl)propionate

The following intermediates were prepared by the method of intermediateB41:

No. Precursors Structure Name B45 Int. B43

2-(Methoxymethylene)-3-(1-methylpyrazol-4-yl)-propionic acid B46 Int.B44

2-(Methoxymethylene)-3-(2-(4-morpholino)pyrimidin-5-yl)propionic acid

The following intermediates were prepared by the method of intermediateB42:

No. Precursors Structure Name B47 Int. B45

1-(3-Ethoxycarbonylprop-1-yl)-5-(1-methylpyrazol-4-ylmethyl)-2-thiouracilB48 Int. B46

1-(3-Ethoxycarbonylprop-1-yl)-5-(2-(4-morpholino)-pyrimid-5-ylmethyl)-2-thiouracilIntermediateB50—2-(4-Fluorobenzylthio)-5-((1-methylpyrazol-4-yl)methyl)pyrimidin-4-one

A mixture of 5-((1-methylpyrazol-4-yl)methyl)-2-thiouracil (118 g),4-fluorobenzyl chloride (76.8 g), potassium carbonate (183.5 g), and dryDMF (100 ml) was stirred under argon at 80° C. for 16 hours, then cooledand evaporated. The solid residue was suspended in water (1500 ml) withvigorous stirring, then acidified to pH2 with hydrochloric acid andstirred for a further hour. The white solid was filtered off and washedwith water and ether to obtain the title compound (168 g). ¹H-NMR(d6-DMSO) δ 3.47 (2H, s), 3.81 (3H, s), 4.41 (2H, s), 7.19 (2H, s), 7.29(1H, s), 7.48 (3H, m), 7.84 (1H, s), 12.74 (1H, br.s); MS (APCI+) found(M+1)=331; C₁₆H₁₅FN₄OS requires 330.

IntermediateB51—1-(3-Ethoxycarbonylprop-1-yl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-pyrimid-5-ylmethyl)pyrimidin-4-one

Intermediate B24 (1.0 g, 1 equiv) in dichloromethane (60 ml) was treatedwith diisopropylethylamine (0.63 ml, 1.3 equiv) followed by4-fluorobenzyl bromide (0.38 ml, 1.1 equiv), giving an orange solutionwhich was stirred under argon for 4 h, then washed with water, dried andevaporated. Chromatography (silica, 5% ethanol in ethyl acetate) elutedfirst the 2-ethoxypyrimidine impurity, followed by the title compound(0.35 g). ¹H-NMR (CDCl₃) δ 1.25 (3H, t), 2.03 (2H, m), 2.33 (2H, t),3.64 (2H, s) 3.83 (2H, m), 3.99 (3H, s), 4.12 (2H, q), 4.47 (2H, s),6.98 (3H, m), 7.37 (2H, m), 8.46 (2H, s); MS (APCI+) M+1=473;C₂₃H₂₅FN₄O₄S requires 472 (pale waxy solid).

The following intermediates were prepared by the method of intermediateB50:

No Precursors Structure Name B52 Int. B32

2-(4-Fluorobenzylthio)-5-((pyrimid-5-yl)-methyl)pyrimidin-4-one B53 Int.B33

2-(4-Fluorobenzylthio)-5-((2-methoxy-pyrimid-5-yl)methyl)pyrimidin-4-oneB54 Int. B34

2-(4-Fluorobenzylthio)-5-((2-trifluoromethylpyrimid-5-yl)methyl)pyrimidin-4-oneB55 Int. B35

2-(4-Fluorobenzyl)thio-5-(2-(4-morpholino)pyrimid-5-ylmethyl)pyrimidin-4-oneB56 Int. B36

2-(4-Fluorobenzyl)thio-5-(2-dimethylaminopyrimid-5-yl-methyl)pyrimidin-4-oneB57 Int. B33 +3,4-difluoro-benzylchloride

2-(3,4-Difluorobenzylthio)-5-((2-methoxy-pyrimid-5-yl)methyl)pyrimidin-4-oneB58 Int. B37

2-(4-Fluorobenzylthio)-5-((1-(2-methoxy-ethyl)pyrazol-4-yl)methyl)pyrimidin-4-oneB59 Int. B30 +benzylchloride

2-Benzylthio-5-(1-methylpyrazol-4-yl-methyl)pyrimidin-4-one B60 Int. B30+2,6-dimethyl-4-chloromethyl-pyridine

2-(2,6-Dimethylpyrid-4-yl)methylthio-5-(1-methylpyrazol-4-ylmethyl)pyrimidin-4-oneB61 Int. B33 +2,6-dichloro-4-chloromethyl-pyridine

2-(2,6-Dichloropyrid-4-yl)methylthio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-oneB62 Int. B33 +3-chloro-methylpyridine

2-(Pyrid-3-yl)methylthio-5-(2-methoxy-pyrimid-5-ylmethyl)pyrimidin-4-oneB63 Int. B33 +4-chloro-methyl2-methylpyridine

2-(2-Methylthiazol-4-yl)methylthio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-oneB64 Int. B38

2-(4-Fluorobenzylthio)-5-benzylpyrimidin-4-one B65 Int. B39

2-(4-Fluorobenzylthio)-5-(4-chlorobenzyl)-pyrimidin-4-one B66 Int. B30+3,4-difluoro-benzylchloride

2-Benzylthio-5-(1-methylpyrazol-4-yl-methyl)pyrimidin-4-one

The following intermediates were prepared by the method of intermediateB51:

No. Precursors Structure Name B67 Int. B47

1-(3-Ethoxycarbonylprop-1-yl)-2-(4-fluoro-benzyl)thio-5-(1-methylpyrazol-4-ylmethyl)-pyrimidin-4-oneB68 Int. B48

1-(3-Ethoxycarbonylprop-1-yl)-2-(4-fluoro-benzyl)thio-5-(2-(4-morpholino)pyrimid-5-yl-methyl)pyrimidin-4-oneIntermediateB70—1-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5-((1-methylpyrazol-4-yl)methyl)pyrimidin-4-one

A mixture of2-(4-fluorobenzylthio)-5-((1-methylpyrazol-4-yl)methyl)pyrimidin-4-one(175 g), tert-butyl iodoacetate (128.3 g), diisopropylethylamine (101.5ml) and dichloromethane (200 ml) was stirred at room temperature underargon for 48 hours. The solution was washed with aq. sodium bicarbonatethen with aq. ammonium chloride, dried and evaporated to a pale viscousoil. Ethyl acetate (300 ml) was added, the precipitate was filtered offand discarded, and the solution was chromatographed (silica, 2.5%–10%methanol+0.5% aq. ammonia in dichloromethane). Product fractions wereevaporated to an orange solid which solidified on standing (140 g).¹H-NMR (d₆-DMSO) δ 1.36 (9H,s), 3.37 (2H,s), 3.76 (3H,s), 4.42 (2H,s),4.65 (2H,s), 7.13 (2H,m), 7.23 (1H,m), 7.45 (4H,m); MS (APCI+) found(M+1)=445; C₂₂H₂₅FN₄O₃S requires 444.

IntermediateB71—1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-((1-methylpyrazol-4-yl)methyl)-pyrimidin-4-one

1-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5-((1-methylpyrazol-4-yl)methyl)pyrimidin-4-one(96.8 g) was dissolved in dichloromethane (195 ml), cooled in ice/water,and trifluoroacetic acid (130 ml) added slowly with rapid stirring.After a further 36 hours stirring, the solvent was evaporated and theglassy residue triturated with ether; yield 78.6 g. ¹H-NMR (d6-DMSO) δ3.36 (2H, s), 3.76 (3H, s), 4.41 (2H, s), 4.67 (2H, s), 7.14 (2H, m),7.23 (1H, s), 7.43–7.49 (4H, m); MS (APCI+) found (M+1)=389;C₁₈H₁₇FN₄O₃S requires 388.

IntermediateB72—1-Ethoxycarbonylmethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-pyrimidin-4-one

A mixture of intermediate B52 (10 g), ethyl bromoacetate (3.38 ml),diisopropylethylamine (5.84 ml) and dichloromethane (50 ml) was stirredovernight, then the solution was washed sequentially with aqueousammonium chloride and aqueous sodium bicarbonate. Chromatography(silica, 5–10% methanol in ethyl acetate) and trituration with ethergave the desired product (7.02 g). ¹H-NMR (CDCl₃) δ 1.26 (3H, t), 3.71(2H, s), 4.26 (2H, q), 4.46 (2H, s), 4.48 (2H, s), 6.91 (1H, s), 6.98(2H, m), 7.35 (2H, m), 8.70 (2H, s), 9.09 (1H, s); MS(APCI⁺) M+1=415,C₂₀H₁₉FN₄O₃S requires 414. MPt 145.1° C.

IntermediateB73—1-Carboxymethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

0.5M aqueous sodium hydroxide (33.8 ml) was added slowly to a solutionof Intermediate B72 (7.01 g) in dioxan (150 ml). The mixture was stiredfor 2.5 h at room temperature, then the dioxan was evaporated, wateradded, and the mixture acidified with aqueous sodium bisulfate. Theprecipitate was filtered off, washed with water and dried to obtain thedesired product (6.31 g). ¹H-NMR (d₆-DMSO) δ 3.59 (2H, s), 4.41 (2H, s),4.67 (2H, s), 7.11 (2H, m), 7.45 (2H, m), 7.72 (1H, s), 8.70 (2H, s)9.03 (1H, s), 13.55 (1H, bs); MS (APCI−) M−1=385, C₁₈H₁₅FN₄O₃S requires386. MPt 206–207° C.

IntermediateB74—1-Ethoxycarbonylmethyl-2-(4-fluorobenzyl)thio-5-(2-oxopyrimid-5-yl-methyl)pyrimidin-4-one

Prepared from Intermediate B86 by the method of Example 21, except usingonly 2 equivalents of B-bromocatecholborane. ¹H-NMR (d6-DMSO) δ 1.28(3H, t), 4.26 (4H, q), 4.53 (2H, s), 4.90 (2H, s), 7.26 (2H, m), 7.57(2H, m), 7.69 1H, s), 8.25 (2H, br. s); MS (APCI+) found (M+1)=431;C₂₀H₁₉FN₄O₄S requires 430.

IntermediateB75—1-Ethoxycarbonylmethyl-2-(4-fluorobenzyl)thio-5-(1-ethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one

To a solution of Intermediate B74 (3.1 g) in dry dimethylformamide (40ml) under argon was added ethyl iodide (1.4 g) and anhydrous potassiumcarbonate (2.5 g). The mixture was stirred at room temperature for 20 hand the solvent removed in vacuo. The residue was partitioned betweenethyl acetate and water. The organic layer was washed with brine andadded in equal portions to three 10 g silica cartridges. Elution of eachcolumn with EtOAc to 18% MeOH:EtOAc and combining appropriate fractionsgave the title compound (1.5 g). ¹H-NMR (CDCl3) δ 1.27t1.39t), 3.46(2H,s), 3.94 (2H,q), 4.25 (2H,q), 4.48 (2H,s), 4.57 (2H,s), 6.9–7.15(2H,m), 7.21 (1H,s), 7.3–7.4 (2H,m), 7.9 (1H,m), 8.4 (1H,m), MS (APCI+)found (M+1)=459; C₂₂H₂₃FN₄O₄S requires 458.

The following intermediates were prepared by the method of intermediateB70:

No. Precursors Structure Name B76 Int. B57

1-(tert-Butoxycarbonylmethyl)-2-(3,4-difluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-oneB77 Int. B58

1-(tert-Butoxycarbonylmethyl)-2-(4-fluoro-benzylthio)-5-((1-(2-methoxyethyl)pyrazol-4-yl)methyl)pyrimidin-4-oneB78 Int. B60

1-(tert-Butoxycarbonylmethyl)-2-(2,6-dimethylpyrid-4-ylmethylthio)-5-((1-methyl-pyrazol-4-yl)methyl)pyrimidin-4-oneB79 Int. B64

1-(tert-Butoxycarbonylmethyl)-2-(4-fluoro-benzylthio)-5-benzylpyrimidin-4-oneB80 Int. B65

1-(tert-Butoxycarbonylmethyl)-2-(4-fluoro-benzylthio)-5-(4-chlorobenzyl)pyrimidin-4-oneB81 Int. B59

1-(tert-Butoxycarbonylmethyl)-2-benzyl-thio-5-((1-methylpyrazol-4-yl)methyl)-pyrimidin-4-oneB82 Int. B66

1-(tert-Butoxycarbonylmethyl)-2-(3,4-difluorobenzylthio)-5-((1-methylpyrazol-4-yl)methyl)pyrimidin-4-one

The following intermediates were prepared by the method of intermediateB72:

No. Precursors Structure Name B84 Int. B61

1-(Ethoxycarbonylmethyl)-2-(2,6-dichloro-pyrid-4-ylmethylthio)-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-oneB85 Int. B54

1-((Ethoxycarbonylmethyl)-2-(4-fluoro-benzylthio)-5-(2-trifluoromethylpyrimid-5-ylmethyl)pyrimidin-4-oneB86 Int. B53

1-(Ethoxycarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-(2-methoxypyrimid-5-yl-methyl)pyrimidin-4-oneB87 Int. B55

1-(Ethoxycarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-(2-(4-morpholino)pyrimid-5-ylmethyl)pyrimidin-4-oneB88 Int. B56

1-(Ethoxycarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-(2-dimethylaminopyrimid-5-ylmethyl)pyrimidin-4-one

The following intermediates were prepared by the method of intermediatedB71:

No. Precursors Structure Name B89 Int. B81

1-(Carboxymethyl)-2-benzylthio-5-(1-methylpyrazol-4-ylmethyl)pyrimidin-4-oneB90 Int. B76

1-(Carboxymethyl)-2-(3,4-difluorobenzyl)-thio-5-(2-methoxypyrimid-5-ylmethyl)-pyrimidin-4-oneB91 Int. B82

1-(Carboxymethyl)-2-(3,4-difluorobenzyl)-thio-5-(1-methylpyrazol-4-ylmethyl)-pyrimidin-4-oneB92 Int. B78

1-(Carboxymethyl)-2-(2,6-dimethylpyrimid-4-ylmethylthio)-5-((1-methylpyrazol-4-yl)-methyl)pyrimidin-4-oneB93 Int. B79

1-Carboxymethyl-2-(4-fluorobenzylthio)-5-benzylpyrimidin-4-one B94 Int.B80

1-Carboxymethyl-2-(4-fluorobenzylthio)-5-(4-chlorobenzyl)pyrimidin-4-oneB104 Int. B77

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-((1-(2-methoxyethyl)pyrazol-4-yl)methyl)pyrimidin-4-one

The following intermediates were prepared by the method of intermediateB73:

No. Precursors Structure Name B96 Int. B51

1-(3-Carboxyprop-1-yl)-2-(4-fluorobenzyl)-thio-5-(2-methoxypyrimid-5-ylmethyl)-pyrimidin-4-oneB97 Int. B67

1-(3-Carboxyprop-1-yl)-2-(4-fluorobenzyl)-thio-5-(2-methylpyrazol-4-ylmethyl)-pyrimidin-4-oneB98 Int. B85

1-Carboxymethyl-2-(4-fluorobenzylthio)-5-((2-trifluoromethylpyrimid-5-yl)methyl)pyrimidin-4-oneB99 Int. B68

1-(3-Carboxyprop-1-yl)-2-(4-fluorobenzyl)-thio-5-(2-(4-morpholino)pyrimid-5-yl-methyl)pyrimidin-4-oneB100 Int. B75

1-Carboxymethyl-2-(4-fluorobenzyl)thio-5-(1-ethyl-2-oxopyrimid-5-yl-methyl)pyrimidin-4-oneB101 Int. B87

1-(Carboxymethyl)-2-(4-fluorobenzyl)thio-5-(2-(4-morpholino)pyrimid-5-yl-methyl)pyrimidin-4-oneB102 Int. B88

1-(Carboxymethyl)-2-(4-fluorobenzyl)thio-5-(2-dimethylaminopyrimid-5-yl-methyl)pyrimidin-4-oneB103 Int. B84

1-(Carboxymethyl)-2-(2,6-dichloropyrid-4-ylmethylthio)-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-oneB104 Int. B86

1-Carboxymethyl-2-(4-Fluorobenzylthio)-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one

Example 11-(N-Methyl-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methylpyrazol-4-ylmethyl)pyrimidin-4-one

A mixture of Intermediate A2 (0.27 g, 1 equiv), Intermediate B71 (0.45g, 1 equiv), hydroxybenzotriazole (0.018 g, 0.1 equiv),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.25 g, 1.1 equiv) anddichloromethane (15 ml) was stirred at room temperature overnight, thendiluted with dichloromethane and washed with aqueous sodium bicarbonate.The organic layer was applied directly to a 10 g silica cartridge, whichwas eluted with 0–10% methanol in ethyl acetate. Product fractions wereevaporated to an oil, which was triturated with ether to obtain a whitesolid (0.39 g). ¹H-NMR (d₆-DMSO) δ 2.95 and 3.08 (3H, 2Xs), 3.61(2H, m),3.86 (3H, m), 4.46–4.61 (6H, m), 6.74 and 6.80 (1H, 2Xs), 6.91–6.99 (2H,m), 7.21–7.49 (12H, m); MS (APCI+) found (M+1)=602; C₃₂H₂₉ClFN₅O₂Srequires 601.

Example 21-(N-Methyl-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methylpyrazol-4-ylmethyl)pyrimidin-4-one

Prepared from Intermediates A45 and B71 by the method of Example 1.¹H-NMR (DMSO) δ 2.96 (3H,s), 3.39 (2H,m), 3.77 (3H,s), 4.43 (2H, s),4.57 (2H,s), 4.97 (2H,s), 7.12 (3H,m), 7.25 (1H,s), 7.34–7.48 (6H, m),7.62–6.70 (2H,m), 8.84 (4H,m).; MS (APCI+) found (M+1)=636;C₃₃H₂₉F₄N₅O₂S requires 635.

Example 31-(N-(2-Dimethylaminoethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methylpyrazol-4-ylmethyl)pyrimidin-4-onehydrochloride

Prepared from Intermediates A61 and B71 by the method of Example 1.¹H-NMR (CDCl₃) δ 2.95 (3H, s), 2.96(3H, s), 3.19 (2H, m), 3.58 (2H, s),3.87 (3H, s), 3.91 (2H, m), 4.42 (2H, s), 4.68 (2H, s), 4.99 (2H, s),6.88–6.93 (2H, m), 7.25–7.29 (6H, m), 7.36–7.45 (6H, m) 7.62 (1H, s); MS(APCI+) found (M+1)=659; C₃₅H₃₆ClFN₆O₂S requires 658.

Example 41-(N-Methyl-N-(4-(4chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-(4-morpholino)pyrimid-5-ylmethyl)pyrimidin-4-one

A solution of Intermediate A7 (0.23 g, 1 equiv), Intermediate B55 (0.27g, 1 equiv) and diisopropyl-ethylamine (0.10 g, 1.2 equiv) in drydichloromethane (6 ml) was stirred at room temperature under argon for20 h, then diluted with more dichloromethane and washed successivelywith water and aqueous ammonium chloride. Drying and evaporation of theorganic phase, followed by chromatography (silica, 0–5% methanol inethyl acetate) gave the desired product as a pale solid (0.19 g). ¹H-NMR(DMSO-d₆) δ: 2.95 (d, 3H), 3.42 (d, 2H), 3.64 (s, 8H), 4.40 (d, 2H),4.60 (d, 2H), 4.95 (d, 2H), 7.1 (m, 2H), 7.30 (d, 2H), 7.35–7.6 (m, 6H),7.65 (m, 3H), 8.30 (s, 2H). MS (APCI+) Found (M+1)=685/687;C₃₆H₃₄ClFN₆O₃S requires 685.

Example 51-(N-(2-(dimethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride

Prepared from Intermediates A72 and B71 by the method of Example 1.¹H-NMR (CDCl₃) δ 2.98 (3H,s), 2.99 (3H,s), 3.20 (2H,m), 3.60 (2H,s),3.93 (5H,m), 4.42 (3H,s), 4.69(2H,s), 5.00 (2H,s), 6.89 (2H,m), 7.2–7.3(4H,m), 7.47 (4H, m), 7.55 (2H,d), 7.70 (3H,m), 11.7 (1H, br s); MS(APCI+) found (M+1)=693; C₃₆H₃₆F₄N₆O₂S requires 692.

Example 61-(N-(2-(diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one

A mixture of Intermediate A3 (82.7 g, 1 equiv), B71 (101.3 g, 1 equiv),hydroxybenzotriazole (39.9 g, 1 equiv),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (100.0 g, 2 equiv) anddichloromethane (1200 ml) was stirred under argon at room temperatureovernight, then aqueous sodium bicarbonate was added slowly withstirring. The organic layer was separated, the aqueous layer extractedtwice more with dichloromethane, and the combined organic extracts driedover potassium carbonate and evaporated to a brown oil. Trituration withether gave a solid, which was filtered off and purified bychromatography on silica, eluting with methanol/dichloromethane thenwith methanolic ammonia/dichloromethane. Product fractions wereevaporated to a yellow foam (98 g). ¹H-NMR (CDCl₃, rotamer mixture) δ0.9–1.0 (6H,m) δ 2.4–2.6 (6H,m), 3.23/3.52 (4H,2x t), 3.58/3.61 (4H, 2xs), 3.85 (3H,s), 4.46/4.53/4.64/4.82 (6H,4x s), 6.75/6.79 (1H,2x s), 6.9(2H,m), 7.2–7.5 (12H,m); MS (APCI+) found (M+1)=687/689; C₃₇H₄₀ClFN₆O₂Srequires 686/688.

Example 71-(N-(2-(diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride

The free base from Example 6 (8.7 g, 1 equiv) was dissolved indichloromethane (50 ml) and 1M hydrogen chloride in ether (1 equiv) wasadded dropwise under argon. The mixture was evaporated to ca. halfvolume and sonicated to obtain a clear solution, which was transferredto a syringe and added dropwise to ether (200 ml) with vigorousstirring. The white solid was filtered off, washed with ether and driedin vacuo; yield 8.55 g. ¹H-NMR (DMSO, ca 2:1 rotamer mixture) δ1.14–1.24 (6H,m), 3.1 (6H, m), 3.6 (2H,m), 3.76 (3H,s), 4.38/4.45 (2H,2xs), 4.61/4.70 (2H,2x s), 4.98/5.11 (2H,2x s), 6.75/6.79 (1H,2x s),7.1–7.7 (15H,m), 10.15/10.75 (1H,2x br s; MS (APCI+) found(M+1)=687/689; C₃₇H₄₀ClFN₆O₂S requires 686/688.

Example 81-(N-(2-(diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4pyrazolylmethyl)pyrimidin-4-onebitartrate

A solution of L-tartaric acid (0.75 g, 1 equiv) in 2-propanol (12 ml)was added to a solution of the free base from Example 6 (3.43 g, 1equiv) in 2-propanol (25 ml) with stirring. The mixture was evaporatedto ca. one third volume, diluted with ether, then the solid was filteredoff, washed with ether and dried in vacuo; yield 3.87 g. ¹H-NMR (DMSO,ca. 60:40 rotamer mixture) δ 0.9–1.1 (6H,m), 2.5–2.8 (4H,m), 3.2–3.4(6H,m), 3.76 (3H,s), 4.20 (2H,s), 4.39/4.43 (2H,2x s), 4.60/4.67 (2H,2xs), 4.92/5.08 (2H,2x s), 7.1–7.7 (15H,m); MS (APCI+) found(M+1)=687/689; C₃₇H₄₀ClFN₆O₂S requires 686/688.

Example 91-(N-(2-(diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onemaleate

A solution of maleic acid (0.58 g, 1 equiv) in methanol (10 ml) wasadded to a solution of the free base from Example 6 (3.43 g, 1 equiv) inmethanol (10 ml) with stirring. The mixture was evaporated to ca. halfvolume, diluted with ether, then the supernatent decanted off. The oilwas triturated with ether to obtain a solid, which was filtered off,washed with ether and dried in vacuo; yield 3.69 g. ¹H-NMR (DMSO, ca.3:1 rotamer mixture) essentially similar to Example 7, plus δ 2.33(3H,s); MS (APCI+) found (M+1)=687/689; C₃₇H₄₀ClFN₆O₂S requires 686/688.

Example 101-(N-(2-(diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onemesylate

Prepared by the method of example 9, using methanesulfonic acid (0.32ml, 1 equiv) in place of maleic acid; yield 3.59 g. ¹H-NMR (DMSO, ca.3:1 rotamer mixture) essentially similar to Example 7, plus δ 6.03(2H,s); MS (APCI+) found (M+1)=687/689; C₃₇H₄₀ClFN₆O₂S requires 686/688.

Example 111-(N-(2-(diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onetaurocholate

Prepared by the method of example 9, using taurocholic acid (2.57 g, 1equiv) in place of maleic acid; yield 5.56 g. ¹H-NMR (DMSO, ca. 3:1rotamer mixture) essentially similar to Example 7, plus (inter alia) δ0.58 (3H,s), 0.81 (3H,s), 0.91 (3H,d), 1.14 (3H,s); MS (APCI+) found(M+1)=687/689; C₃₇H₄₀ClFN₆O₂S requires 686/688.

Example 121-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one

Prepared from Intermediates A73 and B71 by the method of Example 1.¹H-NMR (CDCl₃, rotamer mixture) δ 0.9–1.0 (6H,m) δ 2.4–2.6 (6H,m),3.24/3.4–3.6 (4H,2x m), 3.85 (3H,s), 4.46/4.53/4.66/4.83 (6H,4x s),6.75/6.8 (1H,2x s), 6.9–7.0 (2H,m), 7.3–7.7 (12H,m); MS (APCI+) found(M+1)=721; C₃₈H₄₀F₄N₆O₂S requires 720.

Example 131-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4onehydrochloride

The free base from Example 12 (0.75 g, 1 equiv) was dissolved indichloromethane (5 ml) and 1M hydrogen chloride in ether (1 equiv) wasadded dropwise under argon, then excess ether was added with vigorousstirring. The white solid was filtered off, washed with ether and driedin vacuo; yield 0.73 g. ¹H-NMR (DMSO, ca. 3:1 rotamer mixture) δ 1.1–1.2(6H,m), 3.1 (6H, m), 3.37 (2H+H₂O,m), 3.66 (2H,m), 3.76 (3H,s),4.37/4.45 (2H,2x s), 4.63/4.72 (2H,2x s), 4.97/5.12 (2H,2x s), 7.1(2H,m), 7.24/7.26 (1H,2x s), 7.4–7.5 (6H,m),6.62/6.71 (2H, 2x d), 7.84(4H,m), 10.1/10.65 (1H,2x br s); MS (APCI+) found (M+1)=721;C₃₈H₄₀F₄N₆O₂S requires 720.

Example 141-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onebitartrate

Prepared from the free base of Example 12 by the method of Example 8.¹H-NMR (DMSO, ca. 60:40 rotamer mixture) δ 0.9–1.0 (6H,m), 2.5–2.8(4H,m), 3.2–3.5 (6H,m), 3.76 (3H,s), 4.19 (2H,s), 4.38/4.43 (2H,2x s),4.62/4.69 (2H,2x s), 4.92/5.10 (2H,2x s), 7.0–7.5 (12H,m), 7.6/7.7 (1H,2x d), 7.84 (2H,m); MS (APCI+) found (M+1)=721; C₃₈H₄₀F₄N₆O₂S requires720.

Example 151-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onecitrate

Free base from Example 12 (0.69 g, 1 equiv) was added to acetone (10 ml)followed by citric acid (0.20 g, 1 equiv). The mixture was warmed todissolve the solids then allowed to cool, whereupon the solids werefiltered off and dried in vacuo; yield 0.80 g, 90%, m.p. 130–133° C.¹H-NMR (d6-DMSO, ca. 1:1 rotamer mixture) essentially similar to Example14, plus δ 2.61 (2H,d); MS (APCI+) found (M+1)=721; C₃₈H₄₀F₄N₆O₂Srequires 720.

Example 161-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onetosylate

Free base from Example 12 (1.0 g, 1 equiv) and tosic acid (0.26 g, 1equiv) were dissolved in acetone (20 ml) at room temperature, thenisopropyl acetate (60 ml) was added with stirring. After stirring for afurther 2 hours, the mixture was allowed to stand overnight then thesolid was filtered off, washed with 3:1 isopropyl acetate/acetone, anddried in vacuo; yield 0.87 g, m p. 147° C. ¹H-NMR (d6-DMSO, ca. 3:1rotamer mixture) essentially similar to Example 13, plus (inter alia) δ2.28 (3H,s); MS (APCI+) found (M+1)=721; C₃₈H₄₀F₄N₆O₂S requires 720

Example 171-(N-(2-(diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one

A mixture of Intermediate A106 (0.523 g, 1 equiv), Intermediate B71(0.473 g, 1 equiv), HATU (0.55 g, 1.2 equiv), diisopropylethylamine(0.622 ml, 2.4 equiv) and dichloromethane (20 ml) was stirred underargon at room temperature overnight, then washed with aqueous ammoniumchloride and aqueous sodium bicarbonate. The organic layer was dried andevaporated, and the free-base product isolated by chromatography(silica, 3–8% methanol in dichloromethane) as a pale foam (0.39 g).¹H-NMR (CDCl₃, major rotamer) δ 0.94 (6H,t), 2.47 (4H,q), 2.58 (2H,m),3.26 (2H,m), 3.61 (2H,s), 3.85 (3H,s), 4.52 (2H,s), 4.66 (2H,s), 4.82(2H,s), 6.78 (1H,s), 6.98 (2H,m), 7.3–7.4 (4H,m), 7.6–7.8 (2H,m), 8.08(2H,m), 8.57 (1H,m); MS (APCI+) found (M+1)=722; C₃₇H₃₉F₄N₇O₂S requires721.

Example 181-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride

The free base from Example 17 (0.373 g, 1 equiv) was dissolved indichloromethane (10 ml), and a solution of hydrogen chloride in ether(0.517 ml, 1.0M solution, 1 equiv) was added dropwise with stirring. Thesolvent was removed in vacuo, and the residue triturated with ether toobtain a white solid (0.362 g). ¹H-NMR (DMSO, ca. 60:40 rotamer mixture)δ 1.1–1.3 (6H,m), 3.77 (3H,s), 4.38/4.43 (2H,s), 4.65/4.76 (2H,s),5.00/5.08 (2H,s), 7.10 (2H,m), 7.25 (1H,m), 7.3–7.5 (4H,m) 7.78 (1H,m),7.87 (2H,d), 7.97/8.06 (1H,d), 8.28 (2H,d), 8.61/8.70 (1H,m); MS (APCI+)found (M+1)=722; C₃₇H₃₉F₄N₇O₂S requires 721.

Example 191-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4onebitartrate

Prepared from the free base of Example 17 by the method of Example 8.¹H-NMR (DMSO, ca. 60:40 rotamer mixture) δ 0.88–1.05 (6H,m), 3.76(3H,s), 4.39/4.42 (2H,s), 4.65/4.74 (2H,s), 4.97/5.10 (2H,s), 7.11(2H,m), 7.25 (1H,m), 7.3–7.5 (4H,m), 7.78 (1H,m), 7.87 (2H,m), 7.98/8.07(1H,d), 8.28 (2H,d), 8.61/8.70 (1H,m); MS (APCI+) found (M+1)=722;C₃₇H₃₉F₄N₇O₂S requires 721.

Example 201-(N-(2-(1-Piperidino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onebitartrate

The free base was prepared from Intermediates A108 and B71 by the methodof Example 1, then converted to bitartrate salt by the method of Example8. ¹H-NMR (DMSO, ca 60:40 rotamer mixture) δ 1.3–1.6 (6H,m) δ 2.3–2.7(6H,m), 3.3–3.6 (4H,m), 3.77 (3H,s), 4.22 (2H,s), 4.37/4.44 (2H,2x s),4.62/4.69 (2H,2x s), 4.88/5.08 (2H,2x s), 7.1–7.5 (12H,m), 7.6/7.7 (1H,2x d), 7.83 (2H,m); MS (APCI+) found (M+1)=733; C₃₉H₄₀F₄N₆O₂S requires732.

Example 211-(N-(Carboxymethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one sodium salt

Example 102 (130 mg) was added to a solution of sodium bicarbonate (16mg) in water (4 ml) and stirred for 1 hour at room temperature. A smallproportion of methanol was added to obtain a clear solution on warmingand sonication. Filtration and lyophilisation gave the desired sodiumsalt as a white solid. ¹H-NMR (DMSO) δ 3.49 (2H,s), 3.76 (3H,s), 4.42(2H,s), 4.85 (2H,s), 7.14 (2H,m), 7.26 (1H,s), 7.36 (3H,m), 7.49 (3H,m),7.60 (2H,m), 7.84 (4H,m); MS (APCI−) found (M+1)=678; C₃₄H₂₉F₄N₅O₄Srequires 679.

Example 221-(N-(2-aminoethyl)-N-(4-(4chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-neohydrochloride

The Boc-protected product was prepared from Intermediates A84 and B71 bythe method of Example 1, then deprotected by suspending in dioxan andtreating with excess hydrogen chloride (4M solution in dioxan). Afterstirring for 1 hour, excess ether was added and stirring continued untila fine white solid was obtained. This was filtered off, washed withether and dried to obtain the crude product, which was purified bychromatography (silica, 10–20% methanol in dichloromethane). ¹H-NMR(DMSO, ca. 60:40 rotamer mixture) δ 2.97/3.04 (2H,m) δ 3.37 (2H,m), 3.55(2H,m), 3.77 (3H,s), 4.36/4.45 (2H,2x s), 4.604.67 (2H,2x s), 4.93/5.09(2H,2x s), 7.0–7.7 (15H,m), 8.05/8.20 (2H,2x br s); MS (APCI+) found(M+1)=733; C₃₉H₄₀F₄N₆O₂S requires 732.

Example 231-(N-Methyl-N-(4-(4clorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-oxopyrimid-5-ylmethyl)pyrimidin-4-one

A mixture of Example 121 (0.73 g, 1.2 mmol), B-bromocatecholborane (1.01g, 5.1 mmol) and dry dichloromethane (20 ml) was stirred under argon atroom temperature overnight, giving a clear orange solution. Water wasadded and stirring continued for 30 min, then the organic layer wasseparated and applied directly to a 10 g silica cartridge, which waseluted with 0–14% methanol in dichloromethane. Product fractions wereevaporated to obtain a pale yellow solid (0.36 g). ¹H-NMR (DMSO) δ2.80–3.06 (3H, 2x s), 3.37 (2H, s), 4.33–4.49 (2H, 2x s), 4.50–4.72 (2H,2x s), 4.87–5.06 (2H, m), 7.04–7.75 (13H, m), 8.19 (2H, s); MS (APCI−)found (M−1)=614; C₃₂H₂₇N₅O₃SFCl requires 615.

The following Examples were made either by the method of Example 1 (EDCcoupling) or Example 15 (HATU coupling); where indicated, the salts weresubsequently prepared by the methods of Examples 7–8 as appropriate:

Ex. No. Precursors Structure Name 30 Int. A2Int. B97

1-(3-(N-methyl-N-(4-(4-chlorophenyl)-benzyl)aminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one31 Int. A120Int. B97

1-(3-(4-(4-fluorophenyl)benzylamino-carbonyl)prop-1-yl)-2-(4-fluoro-benzyl)thio-5-(1-methyl-4-pyrazolyl-methyl)pyrimidin-4-one32 Int. A44Int. B97

1-(3-(N-methyl-N-(4-(4-fluorophenyl)-benzyl)aminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one33 Int. A124Int. B97

1-(3-(4-phenylbenzylaminocarbonyl)-prop-1-yl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one34 Int. A6Int. B99

1-(3-(4-(4-chlorophenyl)benzylamino-carbonyl)prop-1-yl)-2-(4-fluorobenzyl)-thio-5-(2-(4-morpholino)-5-pyrimidyl-methyl)pyrimidin-4-one35 Int. A2Int. B99

1-(3-(N-methyl-N-(4-(4-chlorophenyl)-benzyl)aminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(2-(4-morpholino)-5-pyrimidylmethyl)pyrimidin-4-one36 Int. A6Int. B96

1-(3-(4-(4-chlorophenyl)benzylamino-carbonyl)prop-1-yl)-2-(4-fluorobenzyl)-thio-5-(2-methoxy-5-pyrimidylmethyl)-pyrimidin-4-one37 Int. A2Int. B96

1-(3-(N-methyl-N-(4-(4-chlorophenyl)-benzyl)aminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one38 Int. A120Int. B96

1-(3-(4-(4-fluorophenyl)benzylamino-carbonyl)prop-1-yl)-2-(4-fluorobenzyl)-thio-5-(2-methoxy-5-pyrimidylmethyl)-pyrimidin-4-one39 Int. A44Int. B96

1-(3-(N-methyl-N-(4-(4-fluorophenyl)-benzyl)aminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one40 Int. A124Int. B96

1-(3-(4-phenylbenzylaminocarbonyl)-prop-1-yl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one41 Int. A64Int. B96

1-(3-(N-methyl-N-(2-(4-fluorophenyl)-pyrid-5-ylmethyl)aminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one42 Int. A3Int. B104

1-(N-(2-(diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-(2-methoxyethyl)-4-pyrazolylmethyl)-pyrimidin-4-onebitartrate 43 Int. A73Int. B104

1-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-(2-methoxyethyl)-4-pyrazolyl-methyl)pyrimidin-4-onebitartrate 44 Int. A6Int. B100

1-(4-(4-chlorophenyl)benzylamino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-ethyl-2-oxo-5-pyrimidylmethyl)-pyrimidin-4-one45 Int. A2Int. B100

1-(N-methyl-N-(4-(4-chlorophenyl)-benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-ethyl-2-oxo-5-pyrimidylmethyl)pyrimidin-4-one46 Int. A44Int. B100

1-(N-methyl-N-(4-(4-fluorophenyl)-benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-ethyl-2-oxo-5-pyrimidylmethyl)pyrimidin-4-one47 Int. A2Int. B92

1-(N-methyl-N-(4-(4-chlorophenyl)-benzyl)aminocarbonylmethyl)-2-(2,6-dimethylpyrid-4-yl)methylthio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one48 Int. A3Int. B90

1-(N-(2-(diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(3,4-difluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride 49 Int. A45Int. B90

1-(N-methyl-N-(4-(4-trifluoromethyl-phenyl)benzyl)aminocarbonylmethyl)-2-(3,4-difluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one50 Int. A46Int. B71

1-(N-methyl-N-(4-(4-chlorophenyl)-2-fluorobenzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one51 Int. A56Int. B71

1-(N-methyl-N-(4-(2,4-bis(trifluoro-methyl)phenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one52 Int. A60Int. B71

1-(N-methyl-N-(4-(2,4-difluorophenyl)-benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one53 Int. A59Int. B71

1-(N-methyl-N-(4-(3-chloro-4-fluoro-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one54 Int. A53Int. B71

1-(N-methyl-N-(4-(3-fluoro-4-chlororo-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one55 Int. A107Int. B71

1-(N-(2-(1-piperidino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride 56 Int. A75Int. B71

1-(N-(2-(1-pyrrolidino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride 57 Int. A76Int. B71

1-(N-(2-(4-morpholino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride 58 Int. A95Int. B71

1-(N-(2-(bis(2-hydroxyethyl)amino)-ethyl)-N-(4-(4-chlorophenyl)benzyl)₋aminocarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-(1-methyl-4-pyrazolyl-methyl)pyrimidin-4-one59 Int. A74Int. B71

1-(N-(2-(di-isopropylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride 60 Int. A94Int. B71

1-(N-(2-(N-(2-hydroxyethyl)-N-ethyl-amino)ethyl)-N-(4-(4-chlorophenyl)-benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onebitartrate61 Int. A70Int. B71

1-(N-(2-hydroxyethyl)-N-(4-(4-chloro-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one62 Int. A51Int. B71

1-(N-(2-methoxyethyl)-N-(4-(4-chloro-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one63 Int. A80Int. B71

1-(N-(3-(1-pyrrolidino)propyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride 64 Int. A83Int. B71

1-(N-(3-(4-methyl-1-piperazino)propyl)-N-(4-(4-chlorophenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)-pyrimidin-4-onehydrochloride 65 Int. A82Int. B71

1-(N-(3-(4-morpholino)propyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride 66 Int. A79Int. B71

1-(N-(3-(diethylamino)propyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one67 Int. A62Int. B71

1-(N-(3-(dimethylamino)propyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride 68 Int. A50Int. B71

1-(N-(dimethylaminocarbonylmethyl)-N-(4-(4-chlorophenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)-pyrimidin-4-one69 Int. A48Int. B71

1-(N-ethyl-N-(4-(4-chlorophenyl)-benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one70 Int. A6Int. B71

1-(4-(4-chlorophenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)-pyrimidin-4-one71 Int. A93Int. B71

1-(N-(2-(diethylamino)ethyl)-N-(4-(4-difluoromethoxyphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)-pyrimidin-4-onehydrochloride 72 Int. A120Int. B71

1-(4-(4-fluorophenyl)benzylamino-carbonylmethyl)-2-(4-fluorobenzyl)thi-5-(1-methyl-4-pyrazolylmethyl)-pyrimidin-4-one 73 Int. A44Int. B71

1-(N-methyl-N-(4-(4-fluorophenyl)-benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one74 Int. A54Int. B71

1-(N-methyl-N-(4-(4-methoxyphenyl)-benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one75 Int. A92Int. B71

1-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethoxyphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)-pyrimidin-4-onehydrochloride 76 Int. A71Int. B71

1-(N-(2-hydroxyethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)-pyrimidin-4-one77 Int. A78Int. B71

1-(N-(3-(dimethylamino)propyl)-N-(4-(4-trifluoromethylphenyl)benzyl)-aminocarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-(1-methyl-4-pyrazolyl-methyl)pyrimidin-4-onehydrochloride 78 Int. A97Int. B71

1-(N-(4-methyl-1-piperazinocarbonyl-methyl)-N-(4-(4-trifluoromethylphenyl)-benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride79 Int. A96Int. B71

1-(N-(4-morpholinocarbonylmethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)-aminocarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-(1-methyl-4-pyrazolyl-methyl)pyrimidin-4-one80 Int. A52Int. B71

1-(N-(dimethylaminocarbonylmethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)-aminocarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-(1-methyl-4-pyrazolyl-methyl)pyrimidin-4-one81 Int. A121Int. B71

1-(4-(4-trifluoromethylphenyl)benzyl-aminocarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-(1-methyl-4-pyrazolyl-methyl)pyrimidin-4-one82 Int. A98Int. B71

1-(N-(2-(diethylamino)ethyl)-N-(5-(4-chlorophenyl)pyrid-2-ylmethyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)-pyrimidin-4-onehydrochloride 83 Int. A102Int. B71

1-(N-(2-(dimethylamino)ethyl)-N-(5-(4-trifluoromethoxyphenyl)pyrid-2-yl-methyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one84 Int. A99Int. B71

1-(N-(2-(diethylamino)ethyl)-N-(5-(4-trifluoromethylphenyl)pyrid-2-yl-methyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride85 Int. A101Int. B71

1-(N-(2-(diethylamino)ethyl)-N-(2-(4-chlorophenyl)pyrid-5-ylmethyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)-pyrimidin-4-onehydrochloride 86 Int. A103Int. B71

1-(N-(2-hydroxyethyl)-N-(2-(4-chloro-phenyl)pyrid-5-yl-methyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)-pyrimidin-4-one87 Int. A122Int. B71

1-(2-(4-fluorophenyl)pyrid-5-ylmethyl-aminocarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-(1-methyl-4-pyrazolyl-methyl)pyrimidin-4-one88 Int. A64Int. B71

1-(N-methyl-N-(2-(4-fluorophenyl)-pyrid-5-ylmethyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one89 Int. A100Int. B71

1-(N-(2-(dimethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride90 Int. A104Int. B71

1-(N-(2-(diethylamino)ethyl)-N-(2-(4-chlorophenyl)pyrimid-5-ylmethyl)-aminocarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-(1-methyl-4-pyrazolyl-methyl)pyrimidin-4-onebitartrate 91 Int. A123Int. B71

1-(5-(4-chlorophenyl)thien-2-ylmethyl-aminocarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-(1-methyl-4-pyrazolyl-methyl)pyrimidin-4-one92 Int. A66Int. B71

1-(N-methyl-N-(5-(4-chlorophenyl)-thien-2-ylmethyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one93 Int. A63Int. B71

1-(N-methyl-N-(5-(4-fluorophenyl)-thien-2-ylmethyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one94 Int. A3Int. B89

1-(N-(2-(diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-benzylthio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride95 Int. A83Int. B101

1-(N-(3-(4-methyl-1-piperazino)propyl)-N-(4-(4-chlorophenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-(4-morpholino)-5-pyrimidyl-methyl)pyrimdin-4-onebitartrate 96 Int. A45Int. B101

1-(N-methyl-N-(4-(4-trifluoromethyl-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-(4-morpholino)-5-pyrimidylmethyl)-pyrimidin-4-one97 Int. A83Int. B102

1-(N-(3-(4-methyl-1-piperazino)propyl)-N-(4-(4-chlorophenyl)benzyl)amino-carbonymethyl)-2-(4-fluorobenzyl)thio-5-(2-dimethylamino-5-pyrimidyl-methyl)pyrimidin-4-onebitartrate 98 Int. A2Int. B102

1-(N-methyl-N-(4-(4-chlorophenyl)-benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-dimethylamino-5-pyrimidylmethyl)pyrimidin-4-one99 Int. A45Int. B102

1-(N-methyl-N-(4-(4-trifluoromethyl-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-dimethyl-amino-5-pyrimidylmethyl)pyrimidin-4-one100 Int. A73Int. B103

1-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(2,6-dichloropyrid-4-yl)methylthio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-onebitartrate101 Int. A45Int. B103

1-(N-methyl-N-(4-(4-trifluoromethyl-phenyl)benzyl)aminocarbonylmethyl)-2-(2,6-dichloropyrid-4-yl)methylthio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one102 Int. A160Int. B71

1-(N-(Ethoxycarbonylmethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolyl-methyl)pyrimidin-4-one103 Int. A2Int. B90

1-(N-methyl-N-(4-(4-chlorophenyl)-benzyl)aminocarbonylmethyl)-2-(3,4-difluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one104 Int. A45Int. B90

1-(N-methyl-N-(4-(4-trifluoromethyl-phenyl)benzyl)aminocarbonylmethyl)-2-(3,4-difluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one105 Int. A46Int. B104

1-(N-methyl-N-(4-(4-chlorophenyl)-2-fluorobenzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one106 Int. A58Int. B104

1-(N-methyl-N-(4-(4-trifluoromethyl-phenyl)-2-fluorobenzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one107 Int. A10Int. B104

1-(N-methyl-N-(4-(4-chlorophenyl)-3-fluorobenzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one108 Int. A57Int. B104

1-(N-methyl-N-(4-(2-fluoro-4-trifluoro-methylphenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one109 Int. A60Int. B104

1-(N-methyl-N-(4-(2,4-difluorophenyl)-benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one110 Int. A55Int. B104

1-(N-methyl-N-(4-(2-fluoro-4-chloro-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one111 Int. A59Int. B104

1-(N-methyl-N-(4-(3-chloro-4-fluoro-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one112 Int. A53Int. B104

1-(N-methyl-N-(4-(3-fluoro-4-chloro-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one113 Int. A3Int. B104

1-(N-(2-(diethylamin)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-onehydrochloride 114 Int. A61Int. B104

1-(N-(2-(dimethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-onehydrochloride 115 Int. A70Int. B104

1-(N-(2-hydroxyethyl)-N-(4-(4-chloro-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one116 Int. A51Int. B104

1-(N-(2-methoxyethyl)-N-(4-(4-chloro-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one117 Int. A50Int. B104

1-(N-(dimethylaminocarbonylmethyl)-N-(4-(4-chlorophenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)-pyrimidin-4-one118 Int. A11Int. B104

1-(N-(ethoxycarbonylmethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one119 Int. A48Int. B104

1-(N-ethyl-N-(4-(4-chlorophenyl)-benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one120 Int. A6Int. B104

1-(4-(4-chlorophenyl)benzylamino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)-pyrimidin-4-one121 Int. A2Int. B104

1-(N-methyl-N-(4-(4-chlorophenyl)-benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one122 Int. A120Int. B104

1-(4-(4-fluorophenyl)benzylamino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)-pyrimidin-4-one123 Int. A44Int. B104

1-(N-methyl-N-(4-(4-fluorophenyl)-benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one125 Int. A52Int. B104

1-(N-(dimethylaminocarbonylmethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)-aminocarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-(2-methoxy-5-pyrimidyl-methyl)pyrimidin-4-one126 Int. A45Int. B104

1-(N-methyl-N-(4-(4-trifluoromethyl-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one127 Int. A49Int. B104

1-(N-methyl-N-(2-(3,4-dichlorophenyl)-pyrid-5-ylmethyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one128 Int. A65Int. B104

1-(2-(4-chlorophenyl)pyrid-5-ylmethyl)-aminocarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-(2-methoxy-5-pyrimidyl-methyl)pyrimidin-4-one130 Int. A6Int. B98

1-(4-(4-chlorophenyl)benzylamino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-trifluoromethyl-5-pyrimidyl-methyl)pyrimidin-4-one131 Int. A2Int. B98

1-(N-methyl-N-(4-(4-chlorophenyl)-benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-trifluoromethyl-5-pyrimidylmethyl)pyrimidin-4-one132 Int. A73Int. B94

1-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(4-chlorophenylmethyl)pyrimidin-4-onebitartrate 133 Int. A45Int. B94

1-(N-methyl-N-(4-(4-trifluoromethyl-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(4-chlorophenyl-methyl)pyrimidin-4-one134 Int. A124Int. B73

1-(4-phenylbenzylaminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(5-pyrimidylmethyl)pyrimidin-4-one135 Int. A67Int. B73

1-(N-methyl-N-(4-phenylbenzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(5-pyrimidylmethyl)pyrimidin-4-one136 Int. A73Int. B93

1-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(phenylmethyl)pyrimidin-4-onebitartraze137 Int. A45Int. B93

1-(N-methyl-N-(4-(4-trifluoromethyl-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(phenylmethyl)-pyrimidin-4-one138 Int. A73Int. B101

1-(N-(2-(diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(2-(4-morpholino)pyrimid-5-ylmethyl)-pyrimidin-4-one

The following Examples were made by the method of Example 4; the saltswere subsequently prepared by the methods of Examples 7–8 asappropriate:

Ex. No. Precursors Structure Name 140 Int. A155Int. B63

1-(N-methyl-N-(4-(4-trifluoromethyl-phenyl)benzyl)aminocarbonylmethyl)-2-(2-methylthiazol-4-yl)methylthio-5-(2-methoxy-5-pyrimidylmethyl)-pyrimidin-4-one141 Int. A155Int. B62

1-(N-methyl-N-(4-(4-trifluoromethyl-phenyl)benzyl)aminocarbonylmethyl)-2-(pyrid-3-yl)methylthio-5-(2-methoxy-5-pyrimidyl-methyl)pyrimidin-4-one

The following Examples were made by the method of Example 22; the saltswere subsequently prepared by the methods of Examples 7–8 asappropriate:

Ex. No. Precursors Structure Name 150 Int. A90Int. B71

1-(N-(2-(1-piperazino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride 151 Int. A86Int. B71

1-(N-(2-ethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride 152 Int. A85Int. B71

1-(N-(2-methylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride 153 Int. A91Int. B71

1-(N-(3-(2-oxo-1-piperazino)propyl)-N-(4-(4-chlorophenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride154 Int. A89Int. B71

1-(N-(3-(methylamino)propyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride 155 Int. A88Int. B71

1-(N-(3-aminopropyl)-N-(4-(4-chloro-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onehydrochloride156 Int. A87Int. B71

1-(N-(2-(ethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolyl-methyl)pyrimidin-4-one-bitartrate

The following Example was made by the method of Example 21:

Ex. Precurs No. or Structure Name 157 Ex. 118

1(N-(carboxymethyl)-N-(4-(4-chloro-phenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxy-5-pyrimidylmethyl)pyrimidin-4-one,sodiumsaltBiological Data

-   1. Screen for Lp-PLA₂ inhibition.

Enzyme activity was determined by measuring the rate of turnover of theartificial substrate (A) at 37° C. in 50 mM HEPES(N-2-hydroxyethylpiperazine-N′-2-ethanesulphonic acid) buffer containing150 mM NaCl, pH 7.4.

Assays were performed in 96 well titre plates.

Recombinant Lp PLA2 was purified to homogeneity from baculovirusinfected Sf9 cells, using a zinc chelating column, blue sepharoseaffinity chromatography and an anion exchange column. Followingpurification and ultrafiltration, the enzyme was stored at 6 mg/ml at 4°C. Assay plates of compound or vehicle plus buffer were set up usingautomated robotics to a volume of 170 μl. The reaction was initiated bythe addition of 20 μl of 10× substrate (A) to give a final substrateconcentration of 20 μM and 10 μl of diluted enzyme to a final 0.2 nMLpPLA2.

The reaction was followed at 405 nm and 37° C. for 20 minutes using aplate reader with automatic mixing. The rate of reaction was measured asthe rate of change of absorbance.

Results

The compounds described in the Examples were tested as described aboveand had IC₅₀ values in the range 0.001 to 0.00005 μM.

1. A compound of formula (I):

in which: R¹ is an aryl or heteroaryl group, optionally substituted by1, 2, 3 or 4 substituents which may be the same or different selectedfrom C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy, C₍₁₋₁₈₎alkylthio, arylC₍₁₋₁₈₎alkoxy,hydroxy, halogen, CN, COR⁶, carboxy, COOR⁶, CONR⁹R¹⁰, NR⁶COR⁷,SO₂NR⁹R¹⁰, NR⁶SO₂R⁷, NR⁹R¹⁰, mono to perfluoro-C₍₁₋₄₎alkyl and mono toperfluoro-C₍₁₋₄₎alkoxy, oxo, CH₂COOH or a salt thereof, CH₂COOR⁸,CH₂CONR⁹R¹⁰, CH₂CN, (CH₂₎ _(m)NR⁹R¹⁰, (CH₂)_(m)OH or (CH₂)_(m)OR⁶ wherem is an integer from 1 to 3; R² is an aryl or heteroaryl group,optionally substituted by 1, 2, 3 or 4 substituents which may be thesame or different selected from C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy,C₍₁₋₁₈₎alkylthio, arylC₍₁₋₁₈₎alkoxy, hydroxy, halogen, CN, COR⁶,carboxy, COOR⁶, CONR⁹R¹⁰, NR⁶COR⁷, SO₂NR⁹R¹⁰, NR⁶SO₂R⁷, NR⁹R¹⁰, mono toperfluoro-C₍₁₋₄₎alkyl, mono to perfluoro-C₍₁₋₄₎alkoxy, andarylC₍₁₋₄₎alkyl; R³ is hydrogen or C₍₁₋₄₎alkyl which may beunsubstituted or substituted by hydroxy, OR⁶, COR⁶, carboxy, COOR⁶,CONR⁹R¹⁰, NR⁹R¹⁰, mono- or di-(hydroxyC₍₁₋₆₎alkyl)amino orN-hydroxyC₍₁₋₆₎alkyl-N-C₍₁₋₆₎alkyl amino; R⁴ is an aryl or a heteroarylring optionally substituted by 1, 2, 3 or 4 substituents which may bethe same or different selected from C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy,C₍₁₋₁₈₎alkylthio, arylC₍₁₋₁₈₎alkoxy, hydroxy, halogen, CN, COR⁶,carboxy, COOR⁶, CONR⁹R¹⁰, NR⁶COR⁷, SO₂NR⁹R¹⁰, NR⁶SO₂R⁷, NR⁹R¹⁰, mono toperfluoro-C₍₁₋₄₎alkyl and mono to perfluoro-C₍₁₋₄₎alkoxy; R⁵ is an arylring which is further optionally substituted by 1, 2, 3 or 4substituents which may be the same or different selected fromC₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy, C₍₁₋₁₈₎alkylthio, arylC₍₁₋₁₈₎alkoxy,hydroxy, halogen, CN, COR⁶, carboxy, COOR⁶, CONR⁹R¹⁰, NR⁶COR⁷,SO₂NR⁹R¹⁰, NR⁶SO₂R⁷, NR⁹R¹⁰, mono to perfluoro-C₍₁₋₄₎alkyl and mono toperfluoro-C₍₁₋₄₎alkoxy; R⁶ and R⁷ are independently hydrogen orC₍₁₋₂₀₎alkyl, for instance C₍₁₋₄₎alkyl (e.g. methyl or ethyl); R⁸ isC₍₁₋₄₎alkyl or a pharmaceutically acceptable in vivo hydrolysable estergroup; R⁹ and R¹⁰ which may be the same or different is each selectedfrom hydrogen, C₍₁₋₁₂₎alkyl, CH₂R¹¹, CHR¹²CO₂H or a salt thereof, or R⁹and R¹⁰ together with the nitrogen to which they are attached form a 4-to 7-, preferably 5- to 7-, membered ring optionally containing one ormore further heteroatoms selected from oxygen, nitrogen and sulphur, andoptionally substituted by one or two substituents selected from hydroxy,oxo, C₍₁₋₄₎alkyl, C₍₁₋₄₎alkylCO, or aryl; R¹¹ is COOH or a salt thereof,COOR⁸, CONR⁶R⁷, CN, CH₂OH or CH₂OR⁶; R¹² is an amino acid side chain; nis an integer from 1 to 4, preferably 1 or 3; X is O or S; and Z isCR¹³R¹⁴ where R¹³ and R¹⁴ are each hydrogen or C₍₁₋₄₎alkyl, or R¹³ andR¹⁴ together with the intervening carbon atom form a C₍₃₋₆₎cycloalkylring.
 2. A compound of formula (I) as claimed in claim 1 in which Z isCH₂.
 3. A compound of formula (I) as claimed in claim 1 in which R¹ isan aryl group selected from phenyl and naphthyl or a heteroaryl groupwhich comprises a 5- or 6- membered, monocyclic heteroaryl groupcomprising 1 or 2 nitrogen heteroatoms.
 4. A compound of formula (I) asclaimed in claim 1 in which R¹ is pyrimidyl optionally substituted by 1or 2 substituents selected from oxo, arylC₍₁₋₄₎alkyl, C₍₁₋₆₎alkyl,C₍₃₋₆₎cycloalkyl, hydroxy, C₍₁₋₄₎alkoxy, carboxyC₍₁₋₆₎alkyl,C₍₁₋₆₎alkylcarboxyC₍₁₋₆₎alkyl, di-C₍₁₋₆₎alkylamino, and morpholino; orpyrazolyl optionally substituted by C₍₁₋₆₎alkyl.
 5. A compound asclaimed in claim 4 in which ZR¹ is pyrimid-5-ylmethyl optionallysubstituted by 2-methoxy, 2-trifluoromethyl, 2-(4-morpholino) or2-dimethylamino; 2-oxo-pyrimid-5-ylmethyl or 1-methyl-4-pyrazolylmethyl.6. A compound of formula (I) as claimed in claim 1 in which X is S.
 7. Acompound of formula (I) as claimed in claim 1 in which R² is an arylgroup selected from phenyl and naphthyl or a heteroaryl group selectedfrom pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl,quinolyl, benzothiazolyl, pyridazolyl and pyrazinyl.
 8. A compound offormula (I) as claimed in claim 7 in which R² is phenyl optionallysubstituted by halogen.
 9. A compound of formula (I) as claimed in claim1 in which R³ is selected from hydrogen; and methyl, ethyl and propyl,optionally substituted by amino, C₍₁₋₃₎alkylamino, di C₍₁₋₃₎alkylamino,hydroxyC₍₁₋₃₎alkylamino, hydroxy, C₍₁₋₃₎alkoxy, carboxy,C₍₁₋₃₎alkylcarboxy, and heterocycyl.
 10. A compound of formula (I) asclaimed in claim 1 in which R⁴ is selected from phenyl optionallysubstituted by halogen; thiophene; pyridine; and pyrimidine.
 11. Acompound of formula (I) as claimed in claim 1 in which R⁵ is phenyloptionally substituted by halogen, trifluoromethyl, or trifluoromethoxy.12. A compound of formula (I) as claimed in claim 10 in which R⁴ and R⁵together form a 4-(phenyl)phenyl substituent in which the remote phenylring may be optionally substituted by halogen or trifluoromethyl.
 13. Acompound of formula (I) as claimed in claim 1 selected from the groupconsisting of:1-(N-methyl-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methylpyrazol-4-ylmethyl)pyrimidin-4-one;1-(N-methyl-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methylpyrazol-4-ylmethyl)pyrimidin-4-one;1-(N-(2-dimethylaminoethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methylpyrazol-4-ylmethyl)pyrimidin-4-one;1-(N-methyl-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-(4-morpholino)pyrimid-5-ylmethyl)pyrimidin-4-one;1-(N-(2-(dimethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one;1-(N-(2-(diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one;1-(N-(2-(diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-one;1-(N-(2-(1-piperidino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onebitartrate;1-(N-(carboxymethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-methyl-4-pyrazolylmethyl)pyrimidin-4-onesodium salt; or a pharmaceutically acceptable salt thereof.
 14. Apharmaceutical composition comprising a compound of formula (I) asclaimed in claim 13 and a pharmaceutically acceptable carrier.
 15. Amethod of treating atherosclerosis which method comprises administeringto a patient in need thereof an effective amount of a compound offormula (I) as claimed in claim 1 and a statin.
 16. A process forpreparing a compound of formula (I)

in which: R¹ is an aryl or heteroaryl group, optionally substituted by1, 2, 3 or 4 substituents which may be the same or different selectedfrom C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy, C₍₁₋₁₈₎alkylthio, arylC₍₁₋₁₈₎alkoxy,hydroxy, halogen, CN, COR⁶, carboxy, COOR⁶, CONR⁹R¹⁰, NR⁶COR⁷,SO₂NR⁹R¹⁰, NR⁶SO₂R⁷, NR⁹R¹⁰, mono to perfluoro-C₍₁₋₄₎alky and mono toperfluoro-C₍₁₋₄₎alkoxy, oxo, CH₂COOH or a salt thereof, CH₂COOR⁸,CH₂CONR⁹R¹⁰, CH₂CN, (CH₂)_(m)NR⁹R¹⁰, (CH₂)_(m)OH or (CH₂)_(m)OR⁶ where mis an integer from 1 to 3; R² is an aryl or heteroaryl group, optoinallysubstituted 1, 2, 3 or 4 substituents which may be the same or differentselected from C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy, C₍₁₋₁₈₎alkylthio,arylC₍₁₋₁₈₎alkoxy, hydroxy, halogen, CN, COR⁶, carboxy, COOR⁶, CONR⁹R¹⁰,NR⁶COR⁷, SO₂NR⁹R¹⁰, NR⁶SO₂R⁷, NR⁹R¹⁰, mono toperfluoro-C_((1-4)alkyl, mono to perfluoro-C) ₍₁₋₄₎alkoxy, andarylC₍₁₋₄₎alkyl; R³ is hydrogen or C₍₁₋₄₎alkyl which may beunsubstituted or substituted by hydroxy, OR⁶, COR⁶, carboxy, COOR⁶,CONR⁹R¹⁰, NR⁹R¹⁰, mono- or di-(hydroxyC₍₁₋₆₎alkyl)amino orN-hydroxyC₍₁₋₆₎alkyl-N-C₍₁₋₆₎alkyl amino; R⁴ is an aryl or a heteroarylring optionally substituted by 1, 2, 3 or 4 substituents which may bethe same or different selected from C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy,C₍₁₋₁₈₎alkylthio, arylC₍₁₋₁₈₎alkoxy, hydroxy, halogen, CN, COR⁶,carboxy, COOR⁶, CONR⁹R¹⁰, NR⁶COR⁷, SO₂NR⁹R¹⁰, NR⁶SO₂R⁷, NR⁹R¹⁰, mono toperfluoro-C₍₁₋₄₎alkyl and mono to perfluoro-C₍₁₋₄₎alkoxy; R⁵ is an arylring which is further optionally substituted by 1, 2, 3 or 4substituents which may be the same or different selected fromC₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy, C₍₁₋₁₈₎alkylthio, arylC₍₁₋₁₈₎alkoxy,hydroxy, halogen, CN, COR⁶, carboxy, COOR⁶, CONR⁹R¹⁰, NR⁶COR⁷,SO₂NR⁹R¹⁰, NR⁶SO₂R⁷, NR⁹R¹⁰, mono to perfluoro-C₍₁₋₄₎alkyl and mono toperfluoro-C₍₁₋₄₎alkoxy; R⁶ and R⁷ are independently hydrogen orC₍₁₋₂₀₎alkyl, for instance C₍₁₋₄₎alkyl (e.g. methyl or ethyl); R⁸ isC₍₁₋₄₎alkyl or a pharmaceutically acceptable in vivo hydrolysable estergroup; R⁹ and R¹⁰ which may be the same or different is each selectedfrom hydrogen, C₍₁₋₁₂₎alkyl, CH₂R¹¹, CHR¹²CO₂H or a salt thereof, or R⁹and R¹⁰ together with the nitrogen to which they are attached form a 4-to 7-, preferably 5- to 7-, membered ring optionally containing one ormore further heteroatoms selected from oxygen, nitrogen and sulphur, andoptionally substituted by one or two substituents selected from hydroxy,oxo, C₍₁₋₄₎alkyl, C₍₁₋₄₎alkylCO, or aryl; R¹¹ is COOH or a salt thereof,COOR⁸, CONR⁶R⁷, CN, CH₂OH or CH₂OR⁶; R¹² is an amino acid side chain; nis an integer from 1 to 4, preferably 1 or 3; X is O or S; and Z isCR¹³R¹⁴ where R¹³ and R¹⁴ are each hydrogen or C₍₁₋₄₎alkyl, or R¹³ andR¹⁴ together with the intervening carbon atom form a C₍₃₋₆₎cycloalkylring; which process comprises: (a) reacting a compound of formula (II):

in which X, Y, Z, R¹ and R² are the same as defined herein above forformula (I), with a compound of formula (III):R⁵—R⁴—CH₂NHR³  (III) in which R³, R⁴ and R⁵ are the same as definedherein above for formula (I); under amide forming conditions; (b)reacting a compound of formula (IV):

in which X, Z, R¹ and R² are the same as defined herein above forformula (I), with a compound of formula (V):R⁵—R⁴—CH₂NR³—CO—(CH₂)_(n)-L¹  (V) in which n, R³, R⁴ and R⁵ are the sameas defined herein above for formula (I), and L¹ is a leaving group suchas halogen; in the presence of a base such as a secondary or tertiaryamine, in an inert solvent; (c) when X is S, reacting a compound offormula (VI):

in which n, Z, R¹, R³, R⁴ and R⁵ are the same as defined herein abovefor formula (I), with a compound of formula (VII):R²—CH₂-L¹  (VII) in which R² and L¹ are the same as defined herein abovefor formula (I), in the presence of a base such as a secondary ortertiary amine, in an inert solvent; or (d) when X is O, reacting acompound of formula (VIII):

in which n, Z, R¹, R³, R⁴ and R⁵ are the same as defined herein abovefor formula (I), and L² is a leaving group, with a compound of formula(IX):R²—CH₂—OH  (IX) in which R² is the same as defined herein above forformula (I), in the presence of a base, in an inert solvent.
 17. Apharmaceutical composition comprising a compound of formula (I) asclaimed in claim 1 and a pharmaceutically acceptable carrier.
 18. Amethod of treating atherosclerosis which method comprises administeringto a patient in need thereof an effective amount of a compound offormula (I) as claimed in claim 1 to a patient in need thereof.